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Raynaud’s Phenomenon: A Brief Review of the Underlying Mechanisms

Raynaud’s Phenomenon: A Brief Review of the Underlying Mechanisms fphar-07-00438 November 14, 2016 Time: 16:2 # 1 REVIEW published: 16 November 2016 doi: 10.3389/fphar.2016.00438 Raynaud’s Phenomenon: A Brief Review of the Underlying Mechanisms 1† 2† 3 1 3 Manal M. Fardoun , Joseph Nassif , Khodr Issa , Elias Baydoun * and Ali H. Eid * 1 2 Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon, Department of Obstetrics and Gynecology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Raynaud’s phenomenon (RP) is characterized by exaggerated cold-induced vasoconstriction. This augmented vasoconstriction occurs by virtue of a reflex Edited by: response to cooling via the sympathetic nervous system as well as by local Paul H. Ratz, Virginia Commonwealth University, activation of a adrenoceptors (a -AR). In a cold-initiated, mitochondrion-mediated 2C 2C USA mechanism involving reactive oxygen species and the Rho/ROCK pathway, cytoskeletal Reviewed by: rearrangement in vascular smooth muscle cells orchestrates the translocation of a - 2C Chris R. Triggle, AR to the cell membrane, where this receptor readily interacts with its ligand. Different Weill Cornell Medical College in Qatar, Qatar parameters are involved in this spatial and functional rescue of a -AR. Of notable 2C Robert B. Moreland, relevance is the female hormone, 17b-estradiol, or estrogen. This is consistent with Astellas Pharma Global Development, USA the high prevalence of RP in premenopausal women compared to age-matched males. Thomas J. Eddinger, In addition to dissecting the role of these various players, the contribution of pollution Marquette University, USA as well as genetic background to the onset and prevalence of RP are also discussed. *Correspondence: Ali H. Eid Different therapeutic approaches employed as treatment modalities for this disease are ae81@aub.edu.lb also highlighted and analyzed. The lack of an appropriate animal model for RP mandates Elias Baydoun that more efforts be undertaken in order to better understand and eventually treat this eliasbay1@aub.edu.lb disease. Although several lines of treatment are utilized, it is important to note that These authors have contributed equally to this work. precaution is often effective in reducing severity or frequency of RP attacks. Keywords: Raynaud’s Phenomenon, peripheral vascular disease, alpha 2-adrenergic receptors, estrogen, Specialty section: thermoregulation, Rho kinase This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal INTRODUCTION Frontiers in Pharmacology Cold-induced vasoconstriction of cutaneous arterioles is a normal physiological process that Received: 25 August 2016 Accepted: 03 November 2016 redirects blood from the superficial circulation to internal organs in order to protect the body Published: 16 November 2016 from excessive heat loss (Charkoudian, 2010). This constriction is mediated by reflex sympathetic release of norepinephrine (Charkoudian, 2010) as well as increased sensitization of the vasculature Citation: Fardoun MM, Nassif J, Issa K, (Vanhoutte, 1980; Wigley and Flavahan, 2016). When this cold-induced constriction is exaggerated, Baydoun E and Eid AH (2016) it leads to a pathological condition known as Raynaud’s phenomenon (RP) (Herrick, 2012). This Raynaud’s Phenomenon: A Brief disease can be clinically classified as primary or secondary (Block and Sequeira, 2001). Primary RP Review of the Underlying is idiopathic, and it is the most common form of the disease (Roustit et al., 2014). On the other Mechanisms. hand, Secondary RP could be due to myriad of underlying health conditions such as autoimmune Front. Pharmacol. 7:438. diseases or cancer, as well as lifestyle conditions such as smoking or certain medications doi: 10.3389/fphar.2016.00438 Frontiers in Pharmacology | www.frontiersin.org 1 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 2 Fardoun et al. Raynaud’s Phenomenon (Prete et al., 2014). Indeed, 95% of patients suffering from cutaneous vessels, selective potentiation of a -ARs allows their Scleroderma are diagnosed with RP (Black, 1995). cold-induced constrictive effects to overcome the vasodilatory Raynaud’s phenomenon affects up to 10% of the general effects. Accordingly, non-selective a -AR antagonists were, at one population (Garner et al., 2015). Affected individuals suffer from point, used to treat peripheral cold-induced vasoconstriction but cold-provoked vasospastic attacks (Heidrich, 2010) which are were not therapeutically effective (Freedman et al., 1993). associated with the classic triple-color change (pallor, cyanosis, Molecular, genetic, and pharmacologic studies show that and erythema) (Maverakis et al., 2014), in addition to puffiness a -ARs actually comprise three subtypes: a , a , and 2 2A 2B and ulcerations mainly at the level of fingers (Gerbracht et al., a (MacDonald et al., 1997). These subtypes have their 2C 1985). Other distal body organs such as the nose, toes, and corresponding genes on three different chromosomes, and nipples are reported to be affected (Block and Sequeira, 2001; they are all coupled to inhibitory hetero-trimeric G protein Anderson et al., 2004). While there are different manifestations (MacDonald et al., 1997). The search for the particular subtype that can be used to diagnose RP, changes in some parameters responsible for a -AR-mediated cold-induced vasoconstriction may also be helpful. For example, serological tests of RP patients remained unclear for some time. a -ARs did not seem to play 2A show increased levels of endothelin-1 (Zamora et al., 1990), any role in cold-induced constriction (Chotani et al., 2000). Some tumor necrosis factor-a (TNF-a) (Rychlik-Golema et al., 2006), reports pointed to the potential use of a -AR antagonists as a 2B fibrinogen (Spengler et al., 2004), platelet factor (PF-4), and treatment option for vasospasms in RP (MacDonald et al., 1997). von Willebrand’s factor (vWF) (Rychlik-Golema et al., 2006). Much to our surprise, we could not find strong experimental or Magnesium ions and S-nitrosothiols levels appear to decrease in clinical data that support a role for a -AR antagonists in the 2B RP patients compared to unaffected individuals (Leppert et al., treatment of Raynaud’s Disease. 1990; Kundu et al., 2014). Furthermore, anti-centromere and Of the a -AR subtypes, a -AR was thought to be a vestigial 2 2C anti-centriole antibodies are detected in patients’ sera (Gentric receptor for two main reasons. The first is that a -ARs are 2C et al., 1990; Yamada et al., 2014). sequestered in an intracellular compartment (von Zastrow and Many hypotheses have been proposed to dissect and explain Kobilka, 1994), and thus their function was not easily detected the underlying mechanisms implicated in the pathogenesis by immunohistochemistry assays (MacDonald et al., 1997). The of RP. Recent evidence appears to lend strong support for second is that neither the a -AR knockout nor the transgenic 2C the mosaic theory of this disease (Greenstein et al., 1996). mice showed major changes; both remained viable, fertile, and This theory consolidates the multi-etiology of the disease, almost normal (Sallinen et al., 1997). On the other hand, other involving local, neuronal, and hormonal mediators (Wigley, evidence emerged to argue against the apparent vestigiality 2002). Impaired function of any of these mediators may of a -AR. First, a -ARs exhibit highly conserved domains 2C 2C contribute to an exaggerated constriction of cutaneous arteries present in other adrenoceptors (Nyronen et al., 2001). Second, in response to noradrenaline (Easter and Marshall, 2005). the apparently normal phenotype may be due to compensation Noradrenaline elicits its effects through binding to adrenergic by other a -ARs, and third, a -ARs are differentially expressed 2 2C receptors located on the surface of vascular smooth muscle in cells of different tissues (MacDonald et al., 1997). cells (VSMCs) (Guimaraes and Moura, 2001). Typically, VSMCs One interesting and rather unique feature of its biology is that have three types of adrenergic receptors (ARs): a , a , and b . upon certain physiologic and pathophysiologic stimuli, a -AR 1 2 2 2C Depending on the vascular bed, b and b adrenoceptors may can translocate from the endoplasmic reticulum (ER) and Golgi 1 3 also be present but usually with a lower expression than b2 apparatus to the cell membrane. This spatial rescue renders the adrenoceptors (Ahles and Engelhardt, 2014). b adrenoceptors receptor available for its ligand, whose binding then activates the are involved solely in vasodilation (McCance and Huether, 2013), receptor (Chotani et al., 2000, 2004; Jeyaraj et al., 2001). Upon whereas a and a -ARs are responsible for vasoconstriction moderate physiological cooling (i.e., 28 C), a -AR is mobilized 1 2 2C (Figure 1A). While a -ARs have a wide expression pattern from the ER/Golgi to the cell surface (Bailey et al., 2004). The across the vascular tree, a -ARs are predominantly present in now membrane-localized receptors can readily interact with their smaller blood vessels or arterioles (Polonia et al., 1985). At one agonists, become activated and evoke cutaneous vasoconstriction point, these receptors were surprisingly found to be present in response to norepinephrine (Jeyaraj et al., 2001). Indeed, it in the protein extract of minced aortas (Chotani et al., 2004). is now evident that the entirety of cold-induced constriction of However, histochemical analysis showed that these receptors cutaneous arteries is due to an increased activity of a -ARs 2C were expressed in the vasa vasorum of the aorta (Chotani et al., (Bailey et al., 2004; Eid et al., 2008). As such, a -ARs appear 2C 2004). to play an important role in the augmented vasoconstriction Early evidence clearly pointed to the prominent role of observed in RP (Bailey et al., 2004). a -ARs in local cooling-induced constriction of cutaneous The mechanism by which a -AR translocation takes place 2 2C arteries. It is important to note that local cooling causes involves different players such as reactive oxygen species (ROS), vasodilation (Johnson and Kellogg, 2010) as well as inhibits Rho/Rho kinase, and the actin cytoskeleton (Figure 1B). Bailey a -AR-mediated vasoconstriction (Freedman et al., 1992). et al. reported that the Rho/Rho kinase pathway becomes Paradoxically, this very cooling also causes vasoconstriction by activated as early as few minutes after cells get exposed to cold virtue of its potential to selectively amplify a -AR-mediated temperatures (Bailey et al., 2004). The now active Rho evokes constrictive effects (Jeyaraj et al., 2001; Eid et al., 2008). Because the mobilization of a -AR to the membrane, and consequently 2C they play the key role in the sympathetic constriction of triggers cold-induced vasoconstriction (Bailey et al., 2004). Frontiers in Pharmacology | www.frontiersin.org 2 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 3 Fardoun et al. Raynaud’s Phenomenon FIGURE 1 | (A) Predominant adrenergic receptors in arteriolar vascular smooth muscle cells (VSMC). b2AR mediates mediates vasodilation of small microvessels. Vasoconstriction of these vessels occurs via a1-AR, a -AR, and a -AR. Whereas a1-, a -, and b -ARs in these cells are localized at the cell surface, a -AR (in 2A 2 C 2A 2 2 C dotted orange circle) is uniquely trapped intracellularly (mostly trans-Golgi). However, it can be mobilized to the membrane by various stimuli such as cold temperatures. a -AR mediates cold-induced vasoconstriction, which when exacerbated may lead to Raynaud’s phenomenon (RP). (B) Mechanism of cold-induced 2 C mobilization of a -AR. In cutaneous arteriolar SMCs, a decrease in temperature is sensed by the mitochondria, which then releases reactive oxygen species (ROS). 2 C ROS, in turn, activates the Rho/ROCK pathway. Subsequent cytoskeletal rearrangements involving F-actin and filamin-2 promote mobilization of a -AR from the 2 C endoplasmic reticulum/Golgi to the cell surface. In this sense, it seems that Rho, rather than a -AR, is and protein trafficking (Fletcher and Mullins, 2010). The 2C the “thermosensor” (Bailey et al., 2004). However, additional translocation of a -ARs, a main player in RP, from the 2C and rather elegant investigations from the Flavahan group ER/Golgi to the cell membrane of VSMCs is critical for their further showed that the mitochondrion is the “thermo-sensitive” activation. This translocation involves many cytoskeletal organelle in VSMCs (Bailey et al., 2005). Indeed, upon cold stress, components such as F-actin and actin/myosin filaments. it is the mitochondria that initiate the process by releasing ROS, It is through modulation of the actomyosin filaments that VSMC contraction and ultimately vasoconstriction which in turn triggers a redox signal that activates the Rho/Rho occur. kinase pathway leading to spatial redistribution and functional Cold-induced, Rho-mediated architectural change occurs activation of a -ARs (Bailey et al., 2005). This cooling-induced 2C by virtue of a rearrangement of the actin superstructure Rho activation may then act through calcium sensitization or via evident by an increase in F-actin, a downstream effector modulation of cytoskeletal architecture (Hall, 1998; Jeyaraj et al., 2001; Chitaley and Webb, 2002). of Rho kinase signaling (Jeyaraj et al., 2012). Interestingly, immunocytochemical analysis shows that intracellular a -AR 2C and F-actin are sometimes found to be co-localized in non- vascular cells (Hurt et al., 2000). In a rather elegant and RP AND THE ACTIN CYTOSKELETON orchestrated series of events, a -ARs then get in close proximity 2C and associate with actin filaments, readying themselves for the The cytoskeleton plays a major role in fundamental cellular trafficking process (Jeyaraj et al., 2012). This intimate association processes like cell division, migration, cell-cell communication, Frontiers in Pharmacology | www.frontiersin.org 3 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 4 Fardoun et al. Raynaud’s Phenomenon FIGURE 2 | Evidence of positive association between estrogen and RP. Accumulating evidence points to an overwhelming association between estrogen and RP. For instance, estrogen increases a -AR but not a -AR in human arteriolar smooth muscle cells. Moreover, females have higher expression of a -AR than 2 2A 2 C C males. Epidemiologically, RP is reported to have remarkably high incidence in premenopausal females or post-menopausal females on estrogen replacement therapy (ERT). appears to be mediated by a direct interaction between a - or pathology (Maricq et al., 1993). Although it is reported 2C ARs and filamin-2, a cross-linker of actin filaments (Motawea that cardiovascular diseases in general are more prevalent in et al., 2013). Indeed, further in silico protein-protein docking men and post-menopausal women (Reslan and Khalil, 2012), examinations confirmed that the interaction between a -AR being a female is among the risk factors of RP (Garner 2C and F-actin occurs via the direct binding of a -AR to filamin, et al., 2015). This conclusion is partly based on a meta- 2C the actin binding protein (Pawlowski et al., 2014). Interestingly, analysis study asserting the much higher prevalence in females this interaction has evolved only in warm blooded animals compared to males (Garner et al., 2015). In particular, the (Pawlowski et al., 2014). Therefore, elucidation of similar protein- incidence is higher in premenopausal versus post-menopausal protein interactions can help establish more efficient therapies women, with an interesting association between the menstrual for exaggerated vasoconstriction. One scenario would include cycle and cold-modulated digital blood flow (Greenstein et al., approaches that seek to disrupt the interaction between a -AR 1996). Further analysis revealed that post-menopausal females 2C and the cytoskeletal component, F-actin. receiving unopposed estrogen replacement therapy (ERT) are more likely to suffer from the disease than post-menopausal women that are not receiving ERT (Mayes, 1999). Together, these findings demonstrate that estrogen may explain the higher RP AND ESTROGEN incidence in premenopausal women (Figure 2). Interestingly, Evidence from epidemiological studies reveals a rather interesting in post-menopausal women receiving opposed estrogen therapy (estrogen and progesterone together), the incidence of RP was finding regarding the prevalence of RP. There is a significantly higher incidence of this disease in females versus age-matched not significantly higher than that in premenopausal women (Fraenkel et al., 1998). This may suggest that progesterone males (Maricq et al., 1993; Garner et al., 2015). Indeed, 70% negates estrogen’s effect in this context, but this remains to be of all American patients suffering from RP are females (Maricq established. et al., 1993). Among patients affected with RP, the ratio of It is worth mentioning that in premenopausal females, premenopausal females compared to age-matched males is close to 9:1 (Belch and Ho, 2001). This clearly illustrates a noradrenaline-mediated vasoconstriction is higher at the mid- menstrual cycle, characterized by relatively high estrogen level, gender-based element in the prevalence of the disease, and thus hints to a potential role of sex hormones in its onset than during the early stage of the cycle (Chan et al., 2001). Frontiers in Pharmacology | www.frontiersin.org 4 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 5 Fardoun et al. Raynaud’s Phenomenon FIGURE 3 | Genetic basis of RP. The genetic basis of RP is supported by familial studies and twin analysis in addition to a reported case of a 1-month male baby diagnosed with the disease. Furthermore, a combination of positive genotypes for both genes encoding glutathione S-transferase M1 and T1 subtypes may have a role in susceptibility to RP. Linkage analysis pinpointed five areas corresponding to three candidate genes (b-subunit of muscle acetylcholine receptor, 1E and 1B serotonin receptors) which could be associated to RP. Moreover, human and rat females of reproductive age exhibit vasoconstriction in rat tail arteries (Eid et al., 2007). A notable higher vascular responsiveness than males (Li et al., 2014). finding is that among the a -ARs, only the a -AR subtype is 2 2C Interestingly, male vascular responsiveness is potentiated differentially expressed in rat tail arteries, with a remarkably when 17b-estradiol is externally supplemented (Li et al., greater expression in females (McNeill et al., 1999). We had also 2014). This implies that estrogen has a direct effect on reported that in human VSMCs, estrogen does not modulate vasoreactivity, though the mechanisms for such potentiation the expression of a -AR (Eid et al., 2007). The Flavahan 2A remain unclear. group had also established that a -AR mediates the entirety 2C The fundamental role of estrogen in regulating body of cold-induced vasoconstriction. We then hypothesized and temperature has been defined (Charkoudian and Stachenfeld, later confirmed that estrogen indeed increases the expression, 2016). Although estrogen has a vasodilatory effect, it may in surface-localization, and function of a -AR (Eid et al., 2007). 2C many instances decrease body temperature (Charkoudian and This estrogen-induced activity of a -AR was followed by a 2C Stachenfeld, 2016). Since RP can be considered a vascular potentiated cold-induced vasoconstrictive response in mouse thermoregulatory control disorder (Flavahan, 2015), the tail arteries (Eid et al., 2007). Collectively, these pieces of implication of estrogen in the disease becomes obvious evidence highlight a positive association between estrogen especially in light of the exaggerated response to cold in and RP. premenopausal women as well as the higher prevalence of RP in younger females. This is further supported by the findings of English et al. that there is a gender difference RP AND GENETIC BACKGROUND in vasomotor activities in response to estrogen, and that this difference may be a critical contributor to the etiology As mentioned earlier, RP is either idiopathic, or secondary to another disease like scleroderma. There have been some of vasospastic diseases (English et al., 2001), such as speculations that genetic predisposition may be a contributor RP. Evidence indicates that estrogen increases a -AR to the onset of this disease (Tan and Arnett, 2000) (Figure 3). 2C expression in VSMCs and that a -AR-mediates cold-induced However, sequencing results showed no mutations in candidate 2C Frontiers in Pharmacology | www.frontiersin.org 5 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 6 Fardoun et al. Raynaud’s Phenomenon genes that are suspected to play a role in the etiology of the disease emotional stress. With the progression of this condition, such (Susol et al., 2000). These candidate genes are the beta subunit vibration can cause increased digital vasospasm even at room of the muscle acetylcholine receptor and the serotonin 1B and temperature (White et al., 2004). Therefore, it is not surprising 1E receptors (Susol et al., 2000). Nonetheless, others continued that vascular symptoms are highly prevalent among workers to suggest that there is a genetic factor contributing to the whose job requires handling vibrating tools (White et al., 2004). prevalence of this disease (Pistorius et al., 2006). This assertion One of the prominent examples of chemical stressors in is supported by familial studies and twin analysis (Pistorius et al., RP is VCM. This monomer is a colorless gas used in the 2006). Recently, there was a reported case of a 1 month male baby manufacturing of plastic, particularly poly vinyl chloride (PVC). diagnosed with RP (Sharathkumar and Castillo-Caro, 2011). In Interestingly, almost one third of workers exposed to PVC suffer light of this case, it was speculated that there could be a genetic from RP (Maricq et al., 1978). Angiography of these patients’ basis of the disease. However, much evidence remains lacking hands showed vascular tone changes and vascular lesions such as before a strong causative link between genetics and RP can be narrowing of the digital arteries (Falappa et al., 1982). This is not affirmed. surprising since angiographic and capillaroscopic examinations Interestingly, studies of RP patients that were exposed to vinyl have shown that exposure to VCM is toxic for the endothelium chloride monomer (VCM) suggest that the interaction between a (Maricq et al., 1976; Falappa et al., 1982). Furthermore, exposure certain genetic background and environmental conditions may to VCM was shown to significantly contribute to acroosteolysis of play a role in increasing the onset of RP in VCM-exposed distal phalanges of hands, which was recurrently associated with individuals (Fontana et al., 2006). In 2006, Fontana et al. symptoms of RP (Wilson et al., 1967). Indeed, and as mentioned (2006) investigated whether there is an association between earlier, a higher prevalence of RP among French workers exposed polymorphisms in glutathione S-transferase M1 and T1 genes to PVC was reported (Fontana et al., 2006). Taken together, these and RP patients exposed to VCM (Fontana et al., 2006). The observations support the notion that a persistent toxic effect of results showed that the combination of positive genotypes for polyvinyl chloride can contribute to the onset and pathogenesis both genes may increase susceptibility to RP (Fontana et al., of RP. 2006). In another study, using 298 microsatellite markers, a two- There are other chemical compounds or even medicinal drugs stage whole genome screen of six extended families having at that are linked to the onset of RP. Some examples include least three RP patients in each family was undertaken (Susol arsenic, nicotine, and the drug gemcitabine. Indeed, a positive et al., 2000). Linkage analysis identified five chromosomal areas correlation seems to exist between Arsenic and RP. A study in of possible linkage. These were mapped to three candidate genes Chile shows that increased prevalence of signs and symptoms (b-subunit of muscle acetylcholine receptor, 1E and 1B serotonin of peripheral vascular disease, including RP, are associated receptors) which could be associated with RP (Susol et al., 2000). with Arsenic-contaminated drinking water (Nordberg et al., This provides evidence of a genetic basis for RP susceptibility. 2014). Contextually, Arsenic-exposed smelter workers exhibit The fact that five possible linkages were highlighted indicates heightened vasospastic reactivity in the fingers, reminiscent of that RP may be an oligogenic rather than monogenic condition. RP (Lagerkvist et al., 1986; Hall, 2002; William and Markowitz, However, more research is needed to ascertain this suggestion, 2007). Together, these findings provide some evidence of arsenic since some of the findings reported may be false positives (Susol being a player in the etiology of RP. et al., 2000). It would, therefore, be interesting to screen in a large Smoking has been long found to positively associate with RP pool of RP patients, for mutations or SNPs in these candidate (Garner et al., 2015). Moreover, nicotine, one main constituent genes. in tobacco, is known to significantly decrease blood flow and increase vascular resistance (Cardelli and Kleinsmith, 1989). It is thus not surprising that nicotine can exacerbate symptoms of RP (Cherniack et al., 2000; Jackson, 2006), so much so that avoiding TOXICOLOGICAL BASIS OF RP nicotine has been suggested as one element in the treatment of Many of the heightened vasoreactivity responses observed in RP of the nipple (Anderson et al., 2004). RP are due to either sympathetic or local causes. Stressors Some drugs such as gemcitabine, a nucleoside analog used such as cold temperatures or emotional anxieties fall under in chemotherapy (Carmichael, 1998), could evoke symptoms the sympathetic category, since they cause vasoconstriction via reminiscent of RP (Yamada et al., 2014). Indeed, when orally noradrenaline. On the other hand, mechanical and chemical administered, it appears to cause pain, swelling, and whitening stresses fall under the “local” category since they directly affect a of the digits, all of which are typical of RP (Carmichael, body organ that will show symptoms of the disease. A prominent 1998). Indeed, a case of RP and digital necrosis after receiving body area that could be affected by these “local” insults would gemcitabine for bladder cancer has been reported (D’Alessandro be the digits. Prolonged exposure to vibration at the level et al., 2003). Furthermore, a scleroderma patient developed of the hand and arm is an example of mechanical stress. digital ischemia after receiving a combined treatment with Also known as vibration-induced white finger, this hand-arm gemcitabine and carboplatin (Clowse and Wigley, 2003). vibration syndrome is indeed one form of secondary RP that Interestingly, the association of gemcitabine chemotherapy is due to occupational hazards (White et al., 2004). Continuous with digital ischemic events appear to be more common insults of the hand and arm by vibrating machines can prime than previously suspected, especially in patients with tobacco- these organs for increased vasospastic attacks upon a thermal or associated cancers (Kuhar et al., 2010). While the mechanisms Frontiers in Pharmacology | www.frontiersin.org 6 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 7 Fardoun et al. Raynaud’s Phenomenon for this gemcitabine-induced vascular insult remain unclear, Traditional pharmacological drugs alleviate RP symptoms it is proposed that endothelial damage as well as thrombotic by reducing vasoconstriction, inducing vasodilatory effect, or microangiopathy (Venat-Bouvet et al., 2003; Holstein et al., 2010) by a yet unclear mechanism. Drugs used for a vasodilatory may be contributing factors. It is important to note that this effect include calcium channel blockers, cyclic guanosine gemcitabine-associated vascular toxicity is rather pronounced in monophosphate (cGMP)-specific phosphodiesterase type-5 scleroderma patients. Similarly, exacerbations of RP symptoms (PDE5) inhibitors, prostacyclins, prostaglandin analogs, and were found to be associated with fluoropyrimidine, namely alpha-1 blockers. Calciumchannel blockers are the most common capecitabine, therapy (Coward et al., 2005). As such, caution and preferred first-line treatment (Halawa, 2001; Thompson should be taken when administering chemotherapeutic agents, and Pope, 2005). However, in the most recent and highly especially gemcitabine, to scleroderma or RP patients. comprehensive Cochrane review where seven randomized trials Chemotherapeutic agents, other than gemcitabine, have involving 296 patients were analyzed, it was concluded that also been associated with RP. For instance, doxorubicin, and oral calcium channel blockers are relatively ineffective in the cyclophosphamide-induced scleroderma cases mostly present treatment of primary RP. Authors of this important review with diffuse sclerosis and RP (Saif et al., 2016). Moreover, conclude that evidence does not support a role of these blockers vincristine-induced dose-dependent RP has been reported in reducing the frequency and severity of attacks (Ennis et al., (Gottschling et al., 2004). Interestingly, a higher prevalence 2016). This is somewhat inconsistent with an earlier meta- of RP is noted when cisplatin is combined with vinblastine analysis which suggested some, albeit small, efficacy of these (Vogelzang et al., 1981). Whether the neurotoxic effects of these blockers in reducing the severity of RP attacks (Thompson and drugs underpins the increase RP prevalence remains poorly Pope, 2005). However, authors of this paper highlighted the determined. It has been suggested that hyperreactivity in the notion that most of the trials included in their meta-analysis were sympathetic outflow may be an underlying cause (Chant, 1987; crossover studies that did not determine order effect, thus likely Olsen et al., 1987). However, this cannot exclude the possibility introducing some bias (Thompson and Pope, 2005). cGMP- that a direct effect on the vasculature of terminal arterioles specific PDE5 inhibitors have been used as well (Caglayan et al., is also possible, especially that the entirety of cold-induced 2006). Indeed, in an open-label pilot study involving 40 patients, vasoconstriction is mediated by vascular a2C-AR, independently it was found that digital flow was significantly improved in RP of any contribution from the endothelial or the sympathetic patients receiving the PDE V inhibitor, vardenafil, treatment nervous system (Kristensen, 1979; Eid et al., 2007, 2008; Wigley (Caglayan et al., 2006). Consistently with this, it was also found and Flavahan, 2016). that PDE5 inhibitors decrease vasospastic attacks and improve Epidemiologic data derived from a long-term study involving digital blood flow (Lee et al., 2014). Indeed, this efficacy of combined treatment with cisplatin, vinblastine, and bleomycin PDE5 inhibitor was reported in a double-blind, randomized, chemotherapy showed that 35–45% of these treated patients cross-over study involving 29 patients that were divided into two developed RP (Hansen and Olsen, 1989). Bleomycin, in groups. One group received udenafil, a PDE V inhibitor, and particular, appears to be the key player in the development of RP the other a calcium channel blocker, amlodipine, over a period in these patients. Indeed, findings of a recent large cross-sectional of 4 weeks. Both treatments showed comparable efficacy in RP study showed that the only significant predictor of persistent treatment in regard to decreasing the severity of vasospastic RP at follow-up after chemotherapy was the bleomycin dose attacks (Lee et al., 2014). In addition, patients receiving the PDE (Glendenning et al., 2010). V inhibitor showed better digital blood flow when compared to those receiving amlodipine (Lee et al., 2014). Prostanoids are reported to decrease the severity and frequency of vasospastic attacks in RP patients. Their efficacy TREATMENT OF RP has been consistently reported in systematic reviews, meta- Significant efforts have been undertaken to better understand analyses as well as in multiple randomized clinical trials (Clifford and treat RP (Lee et al., 2014; Poredos and Poredos, 2016). et al., 1980; Mohrland et al., 1985; Wigley et al., 1994; Pope However, no definitive or specific therapy for this disease has et al., 2000; Scorza et al., 2001; Milio et al., 2006; Kawald yet been approved by the U.S. Food and Drug Administration et al., 2008). For instance, iloprost, a prostacyclin analog was (FDA; Landry, 2013). One of the limiting factors in the war used to treat 13 patients with RP. In addition to reducing against this disease in the incomplete understanding of its ulcerating lesions, iloprost also caused improvement in blood pathophysiology (Landry, 2013), which is further compounded flow in these patients (Rademaker et al., 1987). Moreover, by the lack of appropriate animal models for RP. Moreover, in a double-blind placebo-controlled trial, it was found that a treatment regimen efficacy may depend on the severity and buflomedil causes a reduction in the frequency of attacks, type of the disease, as well as on the degree of vascular but with no effect on Raynaud severity score (Le Quentrec damage. Despite that, some medications or treatment options and Lefebvre, 1991). On the other hand, a Cochrane review that are thought to alleviate symptoms of the disease are being concluded that evidence does not support a benefit for beraprost, employed in the clinic. These options can be collectively classified ketanserin, dazoxiben, and moxisylyte in ameliorating frequency into traditional pharmacological, ethno-pharmacological, non- duration or severity of attacks (Stewart and Morling, 2012). traditional treatments, and most recently surgical intervention However, the authors of this review indicated that the precision (Table 1). of their conclusion is affected by the fact that most of Frontiers in Pharmacology | www.frontiersin.org 7 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 8 Fardoun et al. Raynaud’s Phenomenon TABLE 1 | Various lines of treatment of Raynaud’s disease. Treatment Effectiveness Reference Traditional treatment Calcium channel blockers Effective; first-line of treatment Halawa, 2001; Thompson and Pope, 2005 PTK inhibitors Efficient Furspan et al., 2004, 2005 PDE5 inhibitors Inefficient Lee et al., 2014 Beta-blockers Controversial Marshall et al., 1976Koltringer et al., 1991 Statins Emerging/powerful Abou-Raya et al., 2008 Prostacyclins Efficient Rademaker et al., 1987 ACE inhibitors Variable effect Henness and Wigley, 2007 Endothelin receptor antagonists Variable effect Poredos and Poredos, 2016 Serotonin receptor antagonists Effective Coleiro et al., 2001 Non-Traditional treatment Botulinum toxin type A Efficient Neumeister et al., 2014 Chinese herb Ineffective Wu et al., 2008 Ginkgo biloba Ineffective Muir et al., 2002 Acupuncture Efficient Appiah et al., 1997 Laser therapy Efficient Hirschl et al., 2004 Surgery Thoracic sympathectomy Effective Coveliers et al., 2011 Hand stripping Effective Balogh et al., 2002 Nerve stimulation effective Kaada, 1982 Fat grafting Encouraging results Bank et al., 2014 A summary of the traditional and non-traditional therapies, as well as some surgical interventions. the studies included in their review are poorly designed or and function could play a beneficial role in the treatment executed of systemic scleroderma (SSc) and the associated secondary Angiotensin receptor blockers, ACE (Angiotensin Converting RP. When ETRAs were employed, not all patients responded Enzyme) inhibitors, PTK (protein tyrosine kinase) inhibitors, positively; nonetheless, these antagonists were able to at least and endothelin receptor antagonists (ETRAs) are also employed alleviate the severity and frequency of vasospastic attacks in the treatment of RP owing to their ability to reduce (Poredos and Poredos, 2016). Several studies have looked at vasoconstriction. A clinical trial reported that losartan (50 mg) the effect of ETRAs in the treatment of SSc-associated RP. causes a significant reduction in the severity and frequency of In 2006, the first prospective study investigating the potential spastic episodes (Dziadzio et al., 1999). The therapeutic benefit benefit of ETRAs in RP was published (Selenko-Gebauer et al., of using ACE inhibitors in the management of RP seems to be 2006). The patients involved in this study received bosentan variable (Henness and Wigley, 2007). Some studies have reported for 16-week, after which it was found that severity of RP that they may have minor benefits, albeit to a lesser extent than attacks was significantly reduced. Another observational study traditional therapies (Wood and Ernst, 2006). Indeed, it is not also reported that after a median of 8 weeks of treatment with recommended that angiotensin receptor blockers be replaces with bosentan, severity of RP was also reduced (Funauchi et al., ACE inhibitors for the treatment of RP (Linnemann and Erbe, 2009). Whether beta blockers have a therapeutic value remains 2016). It is important to note here that although enalapril and controversial. One studies involving 102 patients report that the captopril are reported to reduce the number of attacks in primary beta blockers Propranolol, Oxprenolol, and Atenolol disturb the RP, they do not appear to be effective in reducing these attacks microcirculation causing RP as a side effect (Marshall et al., 1976). in secondary RP (Tosi et al., 1987; Janini et al., 1988). Moreover, Consistent with this, a meta-analysis of 13 studies suggests that in a multicenter, randomized, double-blind, placebo-controlled the use of beta blockers is associated with higher incidence of RP trial involving 210 patients, quinapril treatment for up to 3 years (Mohokum et al., 2012). On the other hand, other reports suggest did not show any beneficial effects in reducing the severity that beta blockers could be beneficial particularly because of their of frequency of attacks (Gliddon et al., 2007). The increased ability to reduce blood viscosity (Koltringer et al., 1991). In this phosphorylation of PTK is associated with the a -AR-mediated study, half of the 40 participants involved received metoprolol, 2C vasoconstriction, thus PTK inhibitors may be used to reverse the and showed reduced blood viscosity compared to the control contractile response to cooling, as these studies show that PTK group. Interestingly, a combination treatment of beta blockers phosphorylation is higher in RP patients arterioles in comparison (metoprolol) with calcium channel inhibitors (felodipin) was to ctrl arterioles (Furspan et al., 2004, 2005). However, future shown to be very effective in reducing symptoms of RP (Csiki studies must be done on this interesting type of treatment. et al., 2011). One of the early events thought to play a role in the There are other drugs that appear to have a potential for use vasculopathy of scleroderma is endothelial injury. Because such in the management of RP. These include statins (Abou-Raya injury leads to increased release of the potent vasoconstrictor, et al., 2008) and serotonin receptor antagonists (Coleiro et al., endothlin-1, it was thought that blocking endothelin signaling 2001). Although their mechanism of action is not fully clear, they Frontiers in Pharmacology | www.frontiersin.org 8 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 9 Fardoun et al. Raynaud’s Phenomenon appear to retard vascular injury, lessen severity, and reduce pain nerve stimulation (Kaada, 1982; Balogh et al., 2002; Coveliers associated with RP. et al., 2011). Although invasive, these are considered to be A recent report discussed the potential benefit of using a rather successful in pain reduction and ulcer healing (Landry, 2013). non-traditional approach for the treatment of RP. Botulinum Finally, fat grafting in the patient’s hands is a new and toxin type A (BTX-A) can be locally injected to improve ulcerated rather unconventional surgical therapy for RP patients (Bank digits and alleviate the associated pain (Neumeister et al., 2014). et al., 2014). This novel treatment originated from clinical This improvement may be due to better perfusion and improved improvements observed after fat grafting in hands suffering vascularity; however, the exact mechanism remains unknown. from burns and radiation dermatitis (Rigotti et al., 2007). When Notably, studies have shown that the use of BTX-A could it was later “tested” on a group of RP patients, the results be safe and efficient (Neumeister et al., 2014). In a recent were encouraging and included alleviation of pain, decrease of retrospective study, it was shown that local injection of BTX- ulcers, and decline in cold attacks (Bank et al., 2014). Although A provides great improvement in artery flow velocity, surface the mechanism by which fat grafting caused these effects is temperature, ulcer, and other clinical symptoms (as measured by largely unclear, it is hypothesized that pathways involving visual analog scale; Zhang et al., 2015). Others have also reported neoangiogenesis and stem cells are likely implicated (Bank et al., similar beneficial effects of BTX-A in the management of RP 2014). (Smith et al., 2012; Zhao and Lian, 2015). However, despite all The variability of the treatments and their altered efficacies these interesting and promising results, a recent systemic review calls for urgent and concerted efforts to better understand the concludes that evidence to support the efficacy of BTX-A in molecular mechanisms underlying the disease, as well as to the management of RP remains insufficient. As such, further develop more targeted and efficient drugs. These drugs may research, particularly randomized controlled trials, is needed include blockers of a as well as inhibitors of PTKs and 2ARs to better determine the potential efficacy of this interesting Rho kinase (Lambova and Muller-Ladner, 2009). Indeed, the first approach. proof of concept for ameliorating RP attacks by blocking a - It is worth mentioning that in some patients, the ARs came from a study by Freedman et al. (1995). This paper aforementioned pharmacological drugs may cause several showed that yohimbine, a -AR antagonist, but not prazosin, side effects such as headaches and dizziness. As such, many a -AR antagonist, can significantly attenuate vasospastic attacks patients resort to alternative therapies in the hope of avoiding of RP. More specifically, a double-blind, placebo-controlled, such undesired side effects. Herbal therapies are one common randomized crossover study investigated the efficacy of OPC- approach. Of particular interest in the management of RP is 28326, a selective a-AR antagonist with preferential binding to Ginkgo biloba plant extracts (Muir et al., 2002) or a combination the a -AR subtype, in recovery from cold-induced vasospasm 2C of two Chinese herbal medications, Duhuo-Tisheng Tang and in secondary RP patients. This study showed that OPC-28326 Danggui-Sini Tang (Wu et al., 2008). However, contradictory is able to improve digital blood flow after acute cold challenge reports suggest that that digital vascular response of RP patients in patients with RP secondary to scleroderma (Wise et al., receiving this therapy was not changed in patients consuming 2004). Another phase II, randomized, double-blind, crossover, the above herbal combination (Appiah et al., 1997; Hirschl et al., single-dose, placebo-controlled, study also tested the efficacy 2004; Wu et al., 2008). Acupuncture has also be employed in the of ORM-12741, a potent a -AR antagonist. Interestingly, 2C management of RP. Indeed, a randomized controlled prospective findings of this study were unexpected in that ORM-12741 study concluded that traditional Chinese acupuncture appears prolonged, rather than shortened, the duration of the cold- to be an effective approach in relieving symptoms, particularly induced constriction of digital arteries evident by delayed attack frequency, of primary RP (Appiah et al., 1997). Others rewarming after a cold challenge (Herrick et al., 2014). The have also reported that auricular electroacupuncture could reasons for this rather unexpected result remain unclear and be helpful in reducing severity and frequency of RP attacks thus, further research is warranted to better understand the (Schlager et al., 2011). However, meta-analysis and systematic intriguing biology of a -AR especially as it related to RP 2C review of the literature does not conclusively support the use of pathophysiology. acupuncture in the management of RP (Malenfant et al., 2009; Huisstede et al., 2011). Laser therapy has also received some attention. A randomized CONCLUSION AND PERSPECTIVES placebo-controlled double-blind crossover study involving 48 patients shows that low level laser therapy could reduce frequency Despite the exponentially growing research and biomedical and severity of RP attacks (Hirschl et al., 2004). Findings of this advances, a definitive and curative treatment for RP still poses study are consistent with those of another double-blind study a real and elusive challenge. Although many aspects and factors that appeared in the same year (al-Awami et al., 2004). High- contributing to this disease have been dissected, the molecular peak power laser treatment has also been reported to reduce mechanisms underlying the onset and progression of RP still the frequency and severity of attacks in a patient suffering from require further investigations. This is, in no small part, due to the Scleroderma and RP (St Surin-Lord and Obagi, 2011). multifactorial etiology (hormonal, neuronal, and endothelial) of It is important to note that surgical therapies may be the disease. Another challenge is the absence of an appropriate considered as an option of treatment (Landry, 2013). These animal model of the disease. The fact that a -AR is expressed 2 C therapies include thoracic sympathectomy, hand stripping, and in many brain regions such as the olfactory bulb and the cerebral Frontiers in Pharmacology | www.frontiersin.org 9 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 10 Fardoun et al. Raynaud’s Phenomenon cortex further complicates the hunt for an RP-specific drug. This AUTHOR CONTRIBUTIONS is especially challenging because a -ARs are also implicated 2C in presynaptic regulation of the heart. Thus, targeting a -ARs All authors contributed to the writing. AHE conceived, designed, 2C in an attempt to treat RP would not be most suitable, since it and revised the manuscript. will affect the heart and brain as well. However, it is tempting to speculate that applying topical creams containing a -ARs 2C blockers to affected body parts could be beneficial, and likely with ACKNOWLEDGMENT fewer side effects. However, rigorous basic research and clinical trials are needed to support this suggestion. So far, precaution is The authors would like to thank Ms. Tuqa Saleh Al-Shehabi for often effective in reducing cold-induced vasospastic attacks of RP. her assistance in drawing the figures. Charkoudian, N. (2010). 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Somlyo, and Copyright © 2016 Fardoun, Nassif, Issa, Baydoun and Eid. This is an open-access H. V. Sparks (Washington, DC: The American Physiological Society), 443–474. article distributed under the terms of the Creative Commons Attribution License Venat-Bouvet, L., Ly, K., Szelag, J. C., Martin, J., Labourey, J. L., Genet, D., (CC BY). The use, distribution or reproduction in other forums is permitted, provided et al. (2003). Thrombotic microangiopathy and digital necrosis: two the original author(s) or licensor are credited and that the original publication in this unrecognized toxicities of gemcitabine. Anticancer. Drugs 14, 829–832. doi: journal is cited, in accordance with accepted academic practice. No use, distribution 10.1097/01.cad.0000098998.92896.01 or reproduction is permitted which does not comply with these terms. 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Raynaud’s Phenomenon: A Brief Review of the Underlying Mechanisms

Frontiers in Pharmacology , Volume 7 – Nov 16, 2016

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fphar-07-00438 November 14, 2016 Time: 16:2 # 1 REVIEW published: 16 November 2016 doi: 10.3389/fphar.2016.00438 Raynaud’s Phenomenon: A Brief Review of the Underlying Mechanisms 1† 2† 3 1 3 Manal M. Fardoun , Joseph Nassif , Khodr Issa , Elias Baydoun * and Ali H. Eid * 1 2 Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon, Department of Obstetrics and Gynecology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Raynaud’s phenomenon (RP) is characterized by exaggerated cold-induced vasoconstriction. This augmented vasoconstriction occurs by virtue of a reflex Edited by: response to cooling via the sympathetic nervous system as well as by local Paul H. Ratz, Virginia Commonwealth University, activation of a adrenoceptors (a -AR). In a cold-initiated, mitochondrion-mediated 2C 2C USA mechanism involving reactive oxygen species and the Rho/ROCK pathway, cytoskeletal Reviewed by: rearrangement in vascular smooth muscle cells orchestrates the translocation of a - 2C Chris R. Triggle, AR to the cell membrane, where this receptor readily interacts with its ligand. Different Weill Cornell Medical College in Qatar, Qatar parameters are involved in this spatial and functional rescue of a -AR. Of notable 2C Robert B. Moreland, relevance is the female hormone, 17b-estradiol, or estrogen. This is consistent with Astellas Pharma Global Development, USA the high prevalence of RP in premenopausal women compared to age-matched males. Thomas J. Eddinger, In addition to dissecting the role of these various players, the contribution of pollution Marquette University, USA as well as genetic background to the onset and prevalence of RP are also discussed. *Correspondence: Ali H. Eid Different therapeutic approaches employed as treatment modalities for this disease are ae81@aub.edu.lb also highlighted and analyzed. The lack of an appropriate animal model for RP mandates Elias Baydoun that more efforts be undertaken in order to better understand and eventually treat this eliasbay1@aub.edu.lb disease. Although several lines of treatment are utilized, it is important to note that These authors have contributed equally to this work. precaution is often effective in reducing severity or frequency of RP attacks. Keywords: Raynaud’s Phenomenon, peripheral vascular disease, alpha 2-adrenergic receptors, estrogen, Specialty section: thermoregulation, Rho kinase This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal INTRODUCTION Frontiers in Pharmacology Cold-induced vasoconstriction of cutaneous arterioles is a normal physiological process that Received: 25 August 2016 Accepted: 03 November 2016 redirects blood from the superficial circulation to internal organs in order to protect the body Published: 16 November 2016 from excessive heat loss (Charkoudian, 2010). This constriction is mediated by reflex sympathetic release of norepinephrine (Charkoudian, 2010) as well as increased sensitization of the vasculature Citation: Fardoun MM, Nassif J, Issa K, (Vanhoutte, 1980; Wigley and Flavahan, 2016). When this cold-induced constriction is exaggerated, Baydoun E and Eid AH (2016) it leads to a pathological condition known as Raynaud’s phenomenon (RP) (Herrick, 2012). This Raynaud’s Phenomenon: A Brief disease can be clinically classified as primary or secondary (Block and Sequeira, 2001). Primary RP Review of the Underlying is idiopathic, and it is the most common form of the disease (Roustit et al., 2014). On the other Mechanisms. hand, Secondary RP could be due to myriad of underlying health conditions such as autoimmune Front. Pharmacol. 7:438. diseases or cancer, as well as lifestyle conditions such as smoking or certain medications doi: 10.3389/fphar.2016.00438 Frontiers in Pharmacology | www.frontiersin.org 1 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 2 Fardoun et al. Raynaud’s Phenomenon (Prete et al., 2014). Indeed, 95% of patients suffering from cutaneous vessels, selective potentiation of a -ARs allows their Scleroderma are diagnosed with RP (Black, 1995). cold-induced constrictive effects to overcome the vasodilatory Raynaud’s phenomenon affects up to 10% of the general effects. Accordingly, non-selective a -AR antagonists were, at one population (Garner et al., 2015). Affected individuals suffer from point, used to treat peripheral cold-induced vasoconstriction but cold-provoked vasospastic attacks (Heidrich, 2010) which are were not therapeutically effective (Freedman et al., 1993). associated with the classic triple-color change (pallor, cyanosis, Molecular, genetic, and pharmacologic studies show that and erythema) (Maverakis et al., 2014), in addition to puffiness a -ARs actually comprise three subtypes: a , a , and 2 2A 2B and ulcerations mainly at the level of fingers (Gerbracht et al., a (MacDonald et al., 1997). These subtypes have their 2C 1985). Other distal body organs such as the nose, toes, and corresponding genes on three different chromosomes, and nipples are reported to be affected (Block and Sequeira, 2001; they are all coupled to inhibitory hetero-trimeric G protein Anderson et al., 2004). While there are different manifestations (MacDonald et al., 1997). The search for the particular subtype that can be used to diagnose RP, changes in some parameters responsible for a -AR-mediated cold-induced vasoconstriction may also be helpful. For example, serological tests of RP patients remained unclear for some time. a -ARs did not seem to play 2A show increased levels of endothelin-1 (Zamora et al., 1990), any role in cold-induced constriction (Chotani et al., 2000). Some tumor necrosis factor-a (TNF-a) (Rychlik-Golema et al., 2006), reports pointed to the potential use of a -AR antagonists as a 2B fibrinogen (Spengler et al., 2004), platelet factor (PF-4), and treatment option for vasospasms in RP (MacDonald et al., 1997). von Willebrand’s factor (vWF) (Rychlik-Golema et al., 2006). Much to our surprise, we could not find strong experimental or Magnesium ions and S-nitrosothiols levels appear to decrease in clinical data that support a role for a -AR antagonists in the 2B RP patients compared to unaffected individuals (Leppert et al., treatment of Raynaud’s Disease. 1990; Kundu et al., 2014). Furthermore, anti-centromere and Of the a -AR subtypes, a -AR was thought to be a vestigial 2 2C anti-centriole antibodies are detected in patients’ sera (Gentric receptor for two main reasons. The first is that a -ARs are 2C et al., 1990; Yamada et al., 2014). sequestered in an intracellular compartment (von Zastrow and Many hypotheses have been proposed to dissect and explain Kobilka, 1994), and thus their function was not easily detected the underlying mechanisms implicated in the pathogenesis by immunohistochemistry assays (MacDonald et al., 1997). The of RP. Recent evidence appears to lend strong support for second is that neither the a -AR knockout nor the transgenic 2C the mosaic theory of this disease (Greenstein et al., 1996). mice showed major changes; both remained viable, fertile, and This theory consolidates the multi-etiology of the disease, almost normal (Sallinen et al., 1997). On the other hand, other involving local, neuronal, and hormonal mediators (Wigley, evidence emerged to argue against the apparent vestigiality 2002). Impaired function of any of these mediators may of a -AR. First, a -ARs exhibit highly conserved domains 2C 2C contribute to an exaggerated constriction of cutaneous arteries present in other adrenoceptors (Nyronen et al., 2001). Second, in response to noradrenaline (Easter and Marshall, 2005). the apparently normal phenotype may be due to compensation Noradrenaline elicits its effects through binding to adrenergic by other a -ARs, and third, a -ARs are differentially expressed 2 2C receptors located on the surface of vascular smooth muscle in cells of different tissues (MacDonald et al., 1997). cells (VSMCs) (Guimaraes and Moura, 2001). Typically, VSMCs One interesting and rather unique feature of its biology is that have three types of adrenergic receptors (ARs): a , a , and b . upon certain physiologic and pathophysiologic stimuli, a -AR 1 2 2 2C Depending on the vascular bed, b and b adrenoceptors may can translocate from the endoplasmic reticulum (ER) and Golgi 1 3 also be present but usually with a lower expression than b2 apparatus to the cell membrane. This spatial rescue renders the adrenoceptors (Ahles and Engelhardt, 2014). b adrenoceptors receptor available for its ligand, whose binding then activates the are involved solely in vasodilation (McCance and Huether, 2013), receptor (Chotani et al., 2000, 2004; Jeyaraj et al., 2001). Upon whereas a and a -ARs are responsible for vasoconstriction moderate physiological cooling (i.e., 28 C), a -AR is mobilized 1 2 2C (Figure 1A). While a -ARs have a wide expression pattern from the ER/Golgi to the cell surface (Bailey et al., 2004). The across the vascular tree, a -ARs are predominantly present in now membrane-localized receptors can readily interact with their smaller blood vessels or arterioles (Polonia et al., 1985). At one agonists, become activated and evoke cutaneous vasoconstriction point, these receptors were surprisingly found to be present in response to norepinephrine (Jeyaraj et al., 2001). Indeed, it in the protein extract of minced aortas (Chotani et al., 2004). is now evident that the entirety of cold-induced constriction of However, histochemical analysis showed that these receptors cutaneous arteries is due to an increased activity of a -ARs 2C were expressed in the vasa vasorum of the aorta (Chotani et al., (Bailey et al., 2004; Eid et al., 2008). As such, a -ARs appear 2C 2004). to play an important role in the augmented vasoconstriction Early evidence clearly pointed to the prominent role of observed in RP (Bailey et al., 2004). a -ARs in local cooling-induced constriction of cutaneous The mechanism by which a -AR translocation takes place 2 2C arteries. It is important to note that local cooling causes involves different players such as reactive oxygen species (ROS), vasodilation (Johnson and Kellogg, 2010) as well as inhibits Rho/Rho kinase, and the actin cytoskeleton (Figure 1B). Bailey a -AR-mediated vasoconstriction (Freedman et al., 1992). et al. reported that the Rho/Rho kinase pathway becomes Paradoxically, this very cooling also causes vasoconstriction by activated as early as few minutes after cells get exposed to cold virtue of its potential to selectively amplify a -AR-mediated temperatures (Bailey et al., 2004). The now active Rho evokes constrictive effects (Jeyaraj et al., 2001; Eid et al., 2008). Because the mobilization of a -AR to the membrane, and consequently 2C they play the key role in the sympathetic constriction of triggers cold-induced vasoconstriction (Bailey et al., 2004). Frontiers in Pharmacology | www.frontiersin.org 2 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 3 Fardoun et al. Raynaud’s Phenomenon FIGURE 1 | (A) Predominant adrenergic receptors in arteriolar vascular smooth muscle cells (VSMC). b2AR mediates mediates vasodilation of small microvessels. Vasoconstriction of these vessels occurs via a1-AR, a -AR, and a -AR. Whereas a1-, a -, and b -ARs in these cells are localized at the cell surface, a -AR (in 2A 2 C 2A 2 2 C dotted orange circle) is uniquely trapped intracellularly (mostly trans-Golgi). However, it can be mobilized to the membrane by various stimuli such as cold temperatures. a -AR mediates cold-induced vasoconstriction, which when exacerbated may lead to Raynaud’s phenomenon (RP). (B) Mechanism of cold-induced 2 C mobilization of a -AR. In cutaneous arteriolar SMCs, a decrease in temperature is sensed by the mitochondria, which then releases reactive oxygen species (ROS). 2 C ROS, in turn, activates the Rho/ROCK pathway. Subsequent cytoskeletal rearrangements involving F-actin and filamin-2 promote mobilization of a -AR from the 2 C endoplasmic reticulum/Golgi to the cell surface. In this sense, it seems that Rho, rather than a -AR, is and protein trafficking (Fletcher and Mullins, 2010). The 2C the “thermosensor” (Bailey et al., 2004). However, additional translocation of a -ARs, a main player in RP, from the 2C and rather elegant investigations from the Flavahan group ER/Golgi to the cell membrane of VSMCs is critical for their further showed that the mitochondrion is the “thermo-sensitive” activation. This translocation involves many cytoskeletal organelle in VSMCs (Bailey et al., 2005). Indeed, upon cold stress, components such as F-actin and actin/myosin filaments. it is the mitochondria that initiate the process by releasing ROS, It is through modulation of the actomyosin filaments that VSMC contraction and ultimately vasoconstriction which in turn triggers a redox signal that activates the Rho/Rho occur. kinase pathway leading to spatial redistribution and functional Cold-induced, Rho-mediated architectural change occurs activation of a -ARs (Bailey et al., 2005). This cooling-induced 2C by virtue of a rearrangement of the actin superstructure Rho activation may then act through calcium sensitization or via evident by an increase in F-actin, a downstream effector modulation of cytoskeletal architecture (Hall, 1998; Jeyaraj et al., 2001; Chitaley and Webb, 2002). of Rho kinase signaling (Jeyaraj et al., 2012). Interestingly, immunocytochemical analysis shows that intracellular a -AR 2C and F-actin are sometimes found to be co-localized in non- vascular cells (Hurt et al., 2000). In a rather elegant and RP AND THE ACTIN CYTOSKELETON orchestrated series of events, a -ARs then get in close proximity 2C and associate with actin filaments, readying themselves for the The cytoskeleton plays a major role in fundamental cellular trafficking process (Jeyaraj et al., 2012). This intimate association processes like cell division, migration, cell-cell communication, Frontiers in Pharmacology | www.frontiersin.org 3 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 4 Fardoun et al. Raynaud’s Phenomenon FIGURE 2 | Evidence of positive association between estrogen and RP. Accumulating evidence points to an overwhelming association between estrogen and RP. For instance, estrogen increases a -AR but not a -AR in human arteriolar smooth muscle cells. Moreover, females have higher expression of a -AR than 2 2A 2 C C males. Epidemiologically, RP is reported to have remarkably high incidence in premenopausal females or post-menopausal females on estrogen replacement therapy (ERT). appears to be mediated by a direct interaction between a - or pathology (Maricq et al., 1993). Although it is reported 2C ARs and filamin-2, a cross-linker of actin filaments (Motawea that cardiovascular diseases in general are more prevalent in et al., 2013). Indeed, further in silico protein-protein docking men and post-menopausal women (Reslan and Khalil, 2012), examinations confirmed that the interaction between a -AR being a female is among the risk factors of RP (Garner 2C and F-actin occurs via the direct binding of a -AR to filamin, et al., 2015). This conclusion is partly based on a meta- 2C the actin binding protein (Pawlowski et al., 2014). Interestingly, analysis study asserting the much higher prevalence in females this interaction has evolved only in warm blooded animals compared to males (Garner et al., 2015). In particular, the (Pawlowski et al., 2014). Therefore, elucidation of similar protein- incidence is higher in premenopausal versus post-menopausal protein interactions can help establish more efficient therapies women, with an interesting association between the menstrual for exaggerated vasoconstriction. One scenario would include cycle and cold-modulated digital blood flow (Greenstein et al., approaches that seek to disrupt the interaction between a -AR 1996). Further analysis revealed that post-menopausal females 2C and the cytoskeletal component, F-actin. receiving unopposed estrogen replacement therapy (ERT) are more likely to suffer from the disease than post-menopausal women that are not receiving ERT (Mayes, 1999). Together, these findings demonstrate that estrogen may explain the higher RP AND ESTROGEN incidence in premenopausal women (Figure 2). Interestingly, Evidence from epidemiological studies reveals a rather interesting in post-menopausal women receiving opposed estrogen therapy (estrogen and progesterone together), the incidence of RP was finding regarding the prevalence of RP. There is a significantly higher incidence of this disease in females versus age-matched not significantly higher than that in premenopausal women (Fraenkel et al., 1998). This may suggest that progesterone males (Maricq et al., 1993; Garner et al., 2015). Indeed, 70% negates estrogen’s effect in this context, but this remains to be of all American patients suffering from RP are females (Maricq established. et al., 1993). Among patients affected with RP, the ratio of It is worth mentioning that in premenopausal females, premenopausal females compared to age-matched males is close to 9:1 (Belch and Ho, 2001). This clearly illustrates a noradrenaline-mediated vasoconstriction is higher at the mid- menstrual cycle, characterized by relatively high estrogen level, gender-based element in the prevalence of the disease, and thus hints to a potential role of sex hormones in its onset than during the early stage of the cycle (Chan et al., 2001). Frontiers in Pharmacology | www.frontiersin.org 4 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 5 Fardoun et al. Raynaud’s Phenomenon FIGURE 3 | Genetic basis of RP. The genetic basis of RP is supported by familial studies and twin analysis in addition to a reported case of a 1-month male baby diagnosed with the disease. Furthermore, a combination of positive genotypes for both genes encoding glutathione S-transferase M1 and T1 subtypes may have a role in susceptibility to RP. Linkage analysis pinpointed five areas corresponding to three candidate genes (b-subunit of muscle acetylcholine receptor, 1E and 1B serotonin receptors) which could be associated to RP. Moreover, human and rat females of reproductive age exhibit vasoconstriction in rat tail arteries (Eid et al., 2007). A notable higher vascular responsiveness than males (Li et al., 2014). finding is that among the a -ARs, only the a -AR subtype is 2 2C Interestingly, male vascular responsiveness is potentiated differentially expressed in rat tail arteries, with a remarkably when 17b-estradiol is externally supplemented (Li et al., greater expression in females (McNeill et al., 1999). We had also 2014). This implies that estrogen has a direct effect on reported that in human VSMCs, estrogen does not modulate vasoreactivity, though the mechanisms for such potentiation the expression of a -AR (Eid et al., 2007). The Flavahan 2A remain unclear. group had also established that a -AR mediates the entirety 2C The fundamental role of estrogen in regulating body of cold-induced vasoconstriction. We then hypothesized and temperature has been defined (Charkoudian and Stachenfeld, later confirmed that estrogen indeed increases the expression, 2016). Although estrogen has a vasodilatory effect, it may in surface-localization, and function of a -AR (Eid et al., 2007). 2C many instances decrease body temperature (Charkoudian and This estrogen-induced activity of a -AR was followed by a 2C Stachenfeld, 2016). Since RP can be considered a vascular potentiated cold-induced vasoconstrictive response in mouse thermoregulatory control disorder (Flavahan, 2015), the tail arteries (Eid et al., 2007). Collectively, these pieces of implication of estrogen in the disease becomes obvious evidence highlight a positive association between estrogen especially in light of the exaggerated response to cold in and RP. premenopausal women as well as the higher prevalence of RP in younger females. This is further supported by the findings of English et al. that there is a gender difference RP AND GENETIC BACKGROUND in vasomotor activities in response to estrogen, and that this difference may be a critical contributor to the etiology As mentioned earlier, RP is either idiopathic, or secondary to another disease like scleroderma. There have been some of vasospastic diseases (English et al., 2001), such as speculations that genetic predisposition may be a contributor RP. Evidence indicates that estrogen increases a -AR to the onset of this disease (Tan and Arnett, 2000) (Figure 3). 2C expression in VSMCs and that a -AR-mediates cold-induced However, sequencing results showed no mutations in candidate 2C Frontiers in Pharmacology | www.frontiersin.org 5 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 6 Fardoun et al. Raynaud’s Phenomenon genes that are suspected to play a role in the etiology of the disease emotional stress. With the progression of this condition, such (Susol et al., 2000). These candidate genes are the beta subunit vibration can cause increased digital vasospasm even at room of the muscle acetylcholine receptor and the serotonin 1B and temperature (White et al., 2004). Therefore, it is not surprising 1E receptors (Susol et al., 2000). Nonetheless, others continued that vascular symptoms are highly prevalent among workers to suggest that there is a genetic factor contributing to the whose job requires handling vibrating tools (White et al., 2004). prevalence of this disease (Pistorius et al., 2006). This assertion One of the prominent examples of chemical stressors in is supported by familial studies and twin analysis (Pistorius et al., RP is VCM. This monomer is a colorless gas used in the 2006). Recently, there was a reported case of a 1 month male baby manufacturing of plastic, particularly poly vinyl chloride (PVC). diagnosed with RP (Sharathkumar and Castillo-Caro, 2011). In Interestingly, almost one third of workers exposed to PVC suffer light of this case, it was speculated that there could be a genetic from RP (Maricq et al., 1978). Angiography of these patients’ basis of the disease. However, much evidence remains lacking hands showed vascular tone changes and vascular lesions such as before a strong causative link between genetics and RP can be narrowing of the digital arteries (Falappa et al., 1982). This is not affirmed. surprising since angiographic and capillaroscopic examinations Interestingly, studies of RP patients that were exposed to vinyl have shown that exposure to VCM is toxic for the endothelium chloride monomer (VCM) suggest that the interaction between a (Maricq et al., 1976; Falappa et al., 1982). Furthermore, exposure certain genetic background and environmental conditions may to VCM was shown to significantly contribute to acroosteolysis of play a role in increasing the onset of RP in VCM-exposed distal phalanges of hands, which was recurrently associated with individuals (Fontana et al., 2006). In 2006, Fontana et al. symptoms of RP (Wilson et al., 1967). Indeed, and as mentioned (2006) investigated whether there is an association between earlier, a higher prevalence of RP among French workers exposed polymorphisms in glutathione S-transferase M1 and T1 genes to PVC was reported (Fontana et al., 2006). Taken together, these and RP patients exposed to VCM (Fontana et al., 2006). The observations support the notion that a persistent toxic effect of results showed that the combination of positive genotypes for polyvinyl chloride can contribute to the onset and pathogenesis both genes may increase susceptibility to RP (Fontana et al., of RP. 2006). In another study, using 298 microsatellite markers, a two- There are other chemical compounds or even medicinal drugs stage whole genome screen of six extended families having at that are linked to the onset of RP. Some examples include least three RP patients in each family was undertaken (Susol arsenic, nicotine, and the drug gemcitabine. Indeed, a positive et al., 2000). Linkage analysis identified five chromosomal areas correlation seems to exist between Arsenic and RP. A study in of possible linkage. These were mapped to three candidate genes Chile shows that increased prevalence of signs and symptoms (b-subunit of muscle acetylcholine receptor, 1E and 1B serotonin of peripheral vascular disease, including RP, are associated receptors) which could be associated with RP (Susol et al., 2000). with Arsenic-contaminated drinking water (Nordberg et al., This provides evidence of a genetic basis for RP susceptibility. 2014). Contextually, Arsenic-exposed smelter workers exhibit The fact that five possible linkages were highlighted indicates heightened vasospastic reactivity in the fingers, reminiscent of that RP may be an oligogenic rather than monogenic condition. RP (Lagerkvist et al., 1986; Hall, 2002; William and Markowitz, However, more research is needed to ascertain this suggestion, 2007). Together, these findings provide some evidence of arsenic since some of the findings reported may be false positives (Susol being a player in the etiology of RP. et al., 2000). It would, therefore, be interesting to screen in a large Smoking has been long found to positively associate with RP pool of RP patients, for mutations or SNPs in these candidate (Garner et al., 2015). Moreover, nicotine, one main constituent genes. in tobacco, is known to significantly decrease blood flow and increase vascular resistance (Cardelli and Kleinsmith, 1989). It is thus not surprising that nicotine can exacerbate symptoms of RP (Cherniack et al., 2000; Jackson, 2006), so much so that avoiding TOXICOLOGICAL BASIS OF RP nicotine has been suggested as one element in the treatment of Many of the heightened vasoreactivity responses observed in RP of the nipple (Anderson et al., 2004). RP are due to either sympathetic or local causes. Stressors Some drugs such as gemcitabine, a nucleoside analog used such as cold temperatures or emotional anxieties fall under in chemotherapy (Carmichael, 1998), could evoke symptoms the sympathetic category, since they cause vasoconstriction via reminiscent of RP (Yamada et al., 2014). Indeed, when orally noradrenaline. On the other hand, mechanical and chemical administered, it appears to cause pain, swelling, and whitening stresses fall under the “local” category since they directly affect a of the digits, all of which are typical of RP (Carmichael, body organ that will show symptoms of the disease. A prominent 1998). Indeed, a case of RP and digital necrosis after receiving body area that could be affected by these “local” insults would gemcitabine for bladder cancer has been reported (D’Alessandro be the digits. Prolonged exposure to vibration at the level et al., 2003). Furthermore, a scleroderma patient developed of the hand and arm is an example of mechanical stress. digital ischemia after receiving a combined treatment with Also known as vibration-induced white finger, this hand-arm gemcitabine and carboplatin (Clowse and Wigley, 2003). vibration syndrome is indeed one form of secondary RP that Interestingly, the association of gemcitabine chemotherapy is due to occupational hazards (White et al., 2004). Continuous with digital ischemic events appear to be more common insults of the hand and arm by vibrating machines can prime than previously suspected, especially in patients with tobacco- these organs for increased vasospastic attacks upon a thermal or associated cancers (Kuhar et al., 2010). While the mechanisms Frontiers in Pharmacology | www.frontiersin.org 6 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 7 Fardoun et al. Raynaud’s Phenomenon for this gemcitabine-induced vascular insult remain unclear, Traditional pharmacological drugs alleviate RP symptoms it is proposed that endothelial damage as well as thrombotic by reducing vasoconstriction, inducing vasodilatory effect, or microangiopathy (Venat-Bouvet et al., 2003; Holstein et al., 2010) by a yet unclear mechanism. Drugs used for a vasodilatory may be contributing factors. It is important to note that this effect include calcium channel blockers, cyclic guanosine gemcitabine-associated vascular toxicity is rather pronounced in monophosphate (cGMP)-specific phosphodiesterase type-5 scleroderma patients. Similarly, exacerbations of RP symptoms (PDE5) inhibitors, prostacyclins, prostaglandin analogs, and were found to be associated with fluoropyrimidine, namely alpha-1 blockers. Calciumchannel blockers are the most common capecitabine, therapy (Coward et al., 2005). As such, caution and preferred first-line treatment (Halawa, 2001; Thompson should be taken when administering chemotherapeutic agents, and Pope, 2005). However, in the most recent and highly especially gemcitabine, to scleroderma or RP patients. comprehensive Cochrane review where seven randomized trials Chemotherapeutic agents, other than gemcitabine, have involving 296 patients were analyzed, it was concluded that also been associated with RP. For instance, doxorubicin, and oral calcium channel blockers are relatively ineffective in the cyclophosphamide-induced scleroderma cases mostly present treatment of primary RP. Authors of this important review with diffuse sclerosis and RP (Saif et al., 2016). Moreover, conclude that evidence does not support a role of these blockers vincristine-induced dose-dependent RP has been reported in reducing the frequency and severity of attacks (Ennis et al., (Gottschling et al., 2004). Interestingly, a higher prevalence 2016). This is somewhat inconsistent with an earlier meta- of RP is noted when cisplatin is combined with vinblastine analysis which suggested some, albeit small, efficacy of these (Vogelzang et al., 1981). Whether the neurotoxic effects of these blockers in reducing the severity of RP attacks (Thompson and drugs underpins the increase RP prevalence remains poorly Pope, 2005). However, authors of this paper highlighted the determined. It has been suggested that hyperreactivity in the notion that most of the trials included in their meta-analysis were sympathetic outflow may be an underlying cause (Chant, 1987; crossover studies that did not determine order effect, thus likely Olsen et al., 1987). However, this cannot exclude the possibility introducing some bias (Thompson and Pope, 2005). cGMP- that a direct effect on the vasculature of terminal arterioles specific PDE5 inhibitors have been used as well (Caglayan et al., is also possible, especially that the entirety of cold-induced 2006). Indeed, in an open-label pilot study involving 40 patients, vasoconstriction is mediated by vascular a2C-AR, independently it was found that digital flow was significantly improved in RP of any contribution from the endothelial or the sympathetic patients receiving the PDE V inhibitor, vardenafil, treatment nervous system (Kristensen, 1979; Eid et al., 2007, 2008; Wigley (Caglayan et al., 2006). Consistently with this, it was also found and Flavahan, 2016). that PDE5 inhibitors decrease vasospastic attacks and improve Epidemiologic data derived from a long-term study involving digital blood flow (Lee et al., 2014). Indeed, this efficacy of combined treatment with cisplatin, vinblastine, and bleomycin PDE5 inhibitor was reported in a double-blind, randomized, chemotherapy showed that 35–45% of these treated patients cross-over study involving 29 patients that were divided into two developed RP (Hansen and Olsen, 1989). Bleomycin, in groups. One group received udenafil, a PDE V inhibitor, and particular, appears to be the key player in the development of RP the other a calcium channel blocker, amlodipine, over a period in these patients. Indeed, findings of a recent large cross-sectional of 4 weeks. Both treatments showed comparable efficacy in RP study showed that the only significant predictor of persistent treatment in regard to decreasing the severity of vasospastic RP at follow-up after chemotherapy was the bleomycin dose attacks (Lee et al., 2014). In addition, patients receiving the PDE (Glendenning et al., 2010). V inhibitor showed better digital blood flow when compared to those receiving amlodipine (Lee et al., 2014). Prostanoids are reported to decrease the severity and frequency of vasospastic attacks in RP patients. Their efficacy TREATMENT OF RP has been consistently reported in systematic reviews, meta- Significant efforts have been undertaken to better understand analyses as well as in multiple randomized clinical trials (Clifford and treat RP (Lee et al., 2014; Poredos and Poredos, 2016). et al., 1980; Mohrland et al., 1985; Wigley et al., 1994; Pope However, no definitive or specific therapy for this disease has et al., 2000; Scorza et al., 2001; Milio et al., 2006; Kawald yet been approved by the U.S. Food and Drug Administration et al., 2008). For instance, iloprost, a prostacyclin analog was (FDA; Landry, 2013). One of the limiting factors in the war used to treat 13 patients with RP. In addition to reducing against this disease in the incomplete understanding of its ulcerating lesions, iloprost also caused improvement in blood pathophysiology (Landry, 2013), which is further compounded flow in these patients (Rademaker et al., 1987). Moreover, by the lack of appropriate animal models for RP. Moreover, in a double-blind placebo-controlled trial, it was found that a treatment regimen efficacy may depend on the severity and buflomedil causes a reduction in the frequency of attacks, type of the disease, as well as on the degree of vascular but with no effect on Raynaud severity score (Le Quentrec damage. Despite that, some medications or treatment options and Lefebvre, 1991). On the other hand, a Cochrane review that are thought to alleviate symptoms of the disease are being concluded that evidence does not support a benefit for beraprost, employed in the clinic. These options can be collectively classified ketanserin, dazoxiben, and moxisylyte in ameliorating frequency into traditional pharmacological, ethno-pharmacological, non- duration or severity of attacks (Stewart and Morling, 2012). traditional treatments, and most recently surgical intervention However, the authors of this review indicated that the precision (Table 1). of their conclusion is affected by the fact that most of Frontiers in Pharmacology | www.frontiersin.org 7 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 8 Fardoun et al. Raynaud’s Phenomenon TABLE 1 | Various lines of treatment of Raynaud’s disease. Treatment Effectiveness Reference Traditional treatment Calcium channel blockers Effective; first-line of treatment Halawa, 2001; Thompson and Pope, 2005 PTK inhibitors Efficient Furspan et al., 2004, 2005 PDE5 inhibitors Inefficient Lee et al., 2014 Beta-blockers Controversial Marshall et al., 1976Koltringer et al., 1991 Statins Emerging/powerful Abou-Raya et al., 2008 Prostacyclins Efficient Rademaker et al., 1987 ACE inhibitors Variable effect Henness and Wigley, 2007 Endothelin receptor antagonists Variable effect Poredos and Poredos, 2016 Serotonin receptor antagonists Effective Coleiro et al., 2001 Non-Traditional treatment Botulinum toxin type A Efficient Neumeister et al., 2014 Chinese herb Ineffective Wu et al., 2008 Ginkgo biloba Ineffective Muir et al., 2002 Acupuncture Efficient Appiah et al., 1997 Laser therapy Efficient Hirschl et al., 2004 Surgery Thoracic sympathectomy Effective Coveliers et al., 2011 Hand stripping Effective Balogh et al., 2002 Nerve stimulation effective Kaada, 1982 Fat grafting Encouraging results Bank et al., 2014 A summary of the traditional and non-traditional therapies, as well as some surgical interventions. the studies included in their review are poorly designed or and function could play a beneficial role in the treatment executed of systemic scleroderma (SSc) and the associated secondary Angiotensin receptor blockers, ACE (Angiotensin Converting RP. When ETRAs were employed, not all patients responded Enzyme) inhibitors, PTK (protein tyrosine kinase) inhibitors, positively; nonetheless, these antagonists were able to at least and endothelin receptor antagonists (ETRAs) are also employed alleviate the severity and frequency of vasospastic attacks in the treatment of RP owing to their ability to reduce (Poredos and Poredos, 2016). Several studies have looked at vasoconstriction. A clinical trial reported that losartan (50 mg) the effect of ETRAs in the treatment of SSc-associated RP. causes a significant reduction in the severity and frequency of In 2006, the first prospective study investigating the potential spastic episodes (Dziadzio et al., 1999). The therapeutic benefit benefit of ETRAs in RP was published (Selenko-Gebauer et al., of using ACE inhibitors in the management of RP seems to be 2006). The patients involved in this study received bosentan variable (Henness and Wigley, 2007). Some studies have reported for 16-week, after which it was found that severity of RP that they may have minor benefits, albeit to a lesser extent than attacks was significantly reduced. Another observational study traditional therapies (Wood and Ernst, 2006). Indeed, it is not also reported that after a median of 8 weeks of treatment with recommended that angiotensin receptor blockers be replaces with bosentan, severity of RP was also reduced (Funauchi et al., ACE inhibitors for the treatment of RP (Linnemann and Erbe, 2009). Whether beta blockers have a therapeutic value remains 2016). It is important to note here that although enalapril and controversial. One studies involving 102 patients report that the captopril are reported to reduce the number of attacks in primary beta blockers Propranolol, Oxprenolol, and Atenolol disturb the RP, they do not appear to be effective in reducing these attacks microcirculation causing RP as a side effect (Marshall et al., 1976). in secondary RP (Tosi et al., 1987; Janini et al., 1988). Moreover, Consistent with this, a meta-analysis of 13 studies suggests that in a multicenter, randomized, double-blind, placebo-controlled the use of beta blockers is associated with higher incidence of RP trial involving 210 patients, quinapril treatment for up to 3 years (Mohokum et al., 2012). On the other hand, other reports suggest did not show any beneficial effects in reducing the severity that beta blockers could be beneficial particularly because of their of frequency of attacks (Gliddon et al., 2007). The increased ability to reduce blood viscosity (Koltringer et al., 1991). In this phosphorylation of PTK is associated with the a -AR-mediated study, half of the 40 participants involved received metoprolol, 2C vasoconstriction, thus PTK inhibitors may be used to reverse the and showed reduced blood viscosity compared to the control contractile response to cooling, as these studies show that PTK group. Interestingly, a combination treatment of beta blockers phosphorylation is higher in RP patients arterioles in comparison (metoprolol) with calcium channel inhibitors (felodipin) was to ctrl arterioles (Furspan et al., 2004, 2005). However, future shown to be very effective in reducing symptoms of RP (Csiki studies must be done on this interesting type of treatment. et al., 2011). One of the early events thought to play a role in the There are other drugs that appear to have a potential for use vasculopathy of scleroderma is endothelial injury. Because such in the management of RP. These include statins (Abou-Raya injury leads to increased release of the potent vasoconstrictor, et al., 2008) and serotonin receptor antagonists (Coleiro et al., endothlin-1, it was thought that blocking endothelin signaling 2001). Although their mechanism of action is not fully clear, they Frontiers in Pharmacology | www.frontiersin.org 8 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 9 Fardoun et al. Raynaud’s Phenomenon appear to retard vascular injury, lessen severity, and reduce pain nerve stimulation (Kaada, 1982; Balogh et al., 2002; Coveliers associated with RP. et al., 2011). Although invasive, these are considered to be A recent report discussed the potential benefit of using a rather successful in pain reduction and ulcer healing (Landry, 2013). non-traditional approach for the treatment of RP. Botulinum Finally, fat grafting in the patient’s hands is a new and toxin type A (BTX-A) can be locally injected to improve ulcerated rather unconventional surgical therapy for RP patients (Bank digits and alleviate the associated pain (Neumeister et al., 2014). et al., 2014). This novel treatment originated from clinical This improvement may be due to better perfusion and improved improvements observed after fat grafting in hands suffering vascularity; however, the exact mechanism remains unknown. from burns and radiation dermatitis (Rigotti et al., 2007). When Notably, studies have shown that the use of BTX-A could it was later “tested” on a group of RP patients, the results be safe and efficient (Neumeister et al., 2014). In a recent were encouraging and included alleviation of pain, decrease of retrospective study, it was shown that local injection of BTX- ulcers, and decline in cold attacks (Bank et al., 2014). Although A provides great improvement in artery flow velocity, surface the mechanism by which fat grafting caused these effects is temperature, ulcer, and other clinical symptoms (as measured by largely unclear, it is hypothesized that pathways involving visual analog scale; Zhang et al., 2015). Others have also reported neoangiogenesis and stem cells are likely implicated (Bank et al., similar beneficial effects of BTX-A in the management of RP 2014). (Smith et al., 2012; Zhao and Lian, 2015). However, despite all The variability of the treatments and their altered efficacies these interesting and promising results, a recent systemic review calls for urgent and concerted efforts to better understand the concludes that evidence to support the efficacy of BTX-A in molecular mechanisms underlying the disease, as well as to the management of RP remains insufficient. As such, further develop more targeted and efficient drugs. These drugs may research, particularly randomized controlled trials, is needed include blockers of a as well as inhibitors of PTKs and 2ARs to better determine the potential efficacy of this interesting Rho kinase (Lambova and Muller-Ladner, 2009). Indeed, the first approach. proof of concept for ameliorating RP attacks by blocking a - It is worth mentioning that in some patients, the ARs came from a study by Freedman et al. (1995). This paper aforementioned pharmacological drugs may cause several showed that yohimbine, a -AR antagonist, but not prazosin, side effects such as headaches and dizziness. As such, many a -AR antagonist, can significantly attenuate vasospastic attacks patients resort to alternative therapies in the hope of avoiding of RP. More specifically, a double-blind, placebo-controlled, such undesired side effects. Herbal therapies are one common randomized crossover study investigated the efficacy of OPC- approach. Of particular interest in the management of RP is 28326, a selective a-AR antagonist with preferential binding to Ginkgo biloba plant extracts (Muir et al., 2002) or a combination the a -AR subtype, in recovery from cold-induced vasospasm 2C of two Chinese herbal medications, Duhuo-Tisheng Tang and in secondary RP patients. This study showed that OPC-28326 Danggui-Sini Tang (Wu et al., 2008). However, contradictory is able to improve digital blood flow after acute cold challenge reports suggest that that digital vascular response of RP patients in patients with RP secondary to scleroderma (Wise et al., receiving this therapy was not changed in patients consuming 2004). Another phase II, randomized, double-blind, crossover, the above herbal combination (Appiah et al., 1997; Hirschl et al., single-dose, placebo-controlled, study also tested the efficacy 2004; Wu et al., 2008). Acupuncture has also be employed in the of ORM-12741, a potent a -AR antagonist. Interestingly, 2C management of RP. Indeed, a randomized controlled prospective findings of this study were unexpected in that ORM-12741 study concluded that traditional Chinese acupuncture appears prolonged, rather than shortened, the duration of the cold- to be an effective approach in relieving symptoms, particularly induced constriction of digital arteries evident by delayed attack frequency, of primary RP (Appiah et al., 1997). Others rewarming after a cold challenge (Herrick et al., 2014). The have also reported that auricular electroacupuncture could reasons for this rather unexpected result remain unclear and be helpful in reducing severity and frequency of RP attacks thus, further research is warranted to better understand the (Schlager et al., 2011). However, meta-analysis and systematic intriguing biology of a -AR especially as it related to RP 2C review of the literature does not conclusively support the use of pathophysiology. acupuncture in the management of RP (Malenfant et al., 2009; Huisstede et al., 2011). Laser therapy has also received some attention. A randomized CONCLUSION AND PERSPECTIVES placebo-controlled double-blind crossover study involving 48 patients shows that low level laser therapy could reduce frequency Despite the exponentially growing research and biomedical and severity of RP attacks (Hirschl et al., 2004). Findings of this advances, a definitive and curative treatment for RP still poses study are consistent with those of another double-blind study a real and elusive challenge. Although many aspects and factors that appeared in the same year (al-Awami et al., 2004). High- contributing to this disease have been dissected, the molecular peak power laser treatment has also been reported to reduce mechanisms underlying the onset and progression of RP still the frequency and severity of attacks in a patient suffering from require further investigations. This is, in no small part, due to the Scleroderma and RP (St Surin-Lord and Obagi, 2011). multifactorial etiology (hormonal, neuronal, and endothelial) of It is important to note that surgical therapies may be the disease. Another challenge is the absence of an appropriate considered as an option of treatment (Landry, 2013). These animal model of the disease. The fact that a -AR is expressed 2 C therapies include thoracic sympathectomy, hand stripping, and in many brain regions such as the olfactory bulb and the cerebral Frontiers in Pharmacology | www.frontiersin.org 9 November 2016 | Volume 7 | Article 438 fphar-07-00438 November 14, 2016 Time: 16:2 # 10 Fardoun et al. Raynaud’s Phenomenon cortex further complicates the hunt for an RP-specific drug. This AUTHOR CONTRIBUTIONS is especially challenging because a -ARs are also implicated 2C in presynaptic regulation of the heart. Thus, targeting a -ARs All authors contributed to the writing. AHE conceived, designed, 2C in an attempt to treat RP would not be most suitable, since it and revised the manuscript. will affect the heart and brain as well. However, it is tempting to speculate that applying topical creams containing a -ARs 2C blockers to affected body parts could be beneficial, and likely with ACKNOWLEDGMENT fewer side effects. However, rigorous basic research and clinical trials are needed to support this suggestion. So far, precaution is The authors would like to thank Ms. Tuqa Saleh Al-Shehabi for often effective in reducing cold-induced vasospastic attacks of RP. her assistance in drawing the figures. Charkoudian, N. (2010). 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Somlyo, and Copyright © 2016 Fardoun, Nassif, Issa, Baydoun and Eid. This is an open-access H. V. Sparks (Washington, DC: The American Physiological Society), 443–474. article distributed under the terms of the Creative Commons Attribution License Venat-Bouvet, L., Ly, K., Szelag, J. C., Martin, J., Labourey, J. L., Genet, D., (CC BY). The use, distribution or reproduction in other forums is permitted, provided et al. (2003). Thrombotic microangiopathy and digital necrosis: two the original author(s) or licensor are credited and that the original publication in this unrecognized toxicities of gemcitabine. Anticancer. Drugs 14, 829–832. doi: journal is cited, in accordance with accepted academic practice. No use, distribution 10.1097/01.cad.0000098998.92896.01 or reproduction is permitted which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org 13 November 2016 | Volume 7 | Article 438

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