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J. Kulka (1964)MICROCIRCULATORY IMPAIRMENT AS A FACTOR IN INFLAMMATORY TISSUE DAMAGE *
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P. Kerkhof, P. Erp (1996)The Role of Epidermal Proliferation in the Pathogenesis of Psoriasis
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Background: Factors initiating capillary conversion in the immunopathogenesis of psoriasis are not well established and quantification of vascular changes in- and outside visible psoriatic plaque has not been studied extensively. Objectives: To assess the pathological involvement of capillaries in the context of well-established features of psoriasis in different phases: symptomless psoriatic skin distant from a lesion (SDL), adjacent to a lesion (SAL), the margin zone of the lesion (ML) and the center of the psoriatic lesion (CL). Methods: In 10 patients with chronic plaque psoriasis, and 10 healthy matched controls, vascular para- meters (vascular tonicity (VD), vascular surface area (VAR), microvascular density (MVD), angiogenesis (pEC)) and hypoxia in the context of well-established features (keratinocyte proliferation, neutrophils and T-cells) were analyzed within the psoriatic lesion and symptomless psoriatic skin, using immunohistochemical markers (Ki67/CD31 double-staining and HIF-1a-, Elastase- and T-Bet-staining). Results: VD and neutrophils were significantly increased in all sites, compared to healthy controls. The VAR, MVD, Ki67þ nuclei, HIF-1a and T-Bet start to augment in the SAL. Within the overt psoriatic plaque angiogenesis increases. Biopsies closer to the center of a plaque, exhibited increased values of the MVD, VAR, VD, Ki67þ nuclei, T-Betþ Th1 cells and neutrophils. Conclusion: In SDL, vasodilatation and activation of the innate immune system (increased neutrophils) was detected. This could indicate that psoriasis is not restricted to lesional skin, but rather is a systemic disease. Closer to the psoriatic plaque, vascular and epithelial proliferation was observed, along with hypoxic cells and activation of the acquired immunity (augmented T-Bet cells). Keywords vasculature, angiogenesis, psoriasis, hypoxia, inflammation growth factor) fulfills an important role in vascular alterations Introduction in psoriasis, while Benhadou et al found that overexpression of The notion that a vascular alteration plays a crucial role in the epidermal VEGF-A functions mediates a psoriasis-like dis- development and maintenance of clinical psoriasis has been 5,6 ease. Consequently, some authors hypothesize that the initial debated for a long time. Modification of the microvasculature stimulus in psoriasis could be vascular alteration including is essential in the maintenance of the psoriasis plaque in pro- dilatation of the cutaneous microcirculation accompanied with viding nutrition to the hyperplastic keratinocytes, dermal tissue migration of inflammatory cells. and enabling migration of inflammatory cells. In contrast, Baverman and Sibley demonstrated that the per- Therefore, the microvasculature in psoriasis has been stud- centage of labeled basal cells in the epidermis was evidently ied during many decades. Auspitz already described the pin- increased prior to the development of tortuous and dilated point bleedings after removing the stratum corneum. Pinkus and Mehregan. described the squirting papilla with elongated dilated capillaries and extravasation of neutrophils, forming Department of Dermatology, Radboud University Medical Center, Nijmegen, micropustules of Kogoi, the pathognomonic sign in the micro- the Netherlands morphology of psoriasis. This phenomenon displays in a focal Corresponding Author: distribution pattern within the psoriatic lesion. Sabina C. A. Hanssen, MD, Department of Dermatology, Radboud University In addition, Kulka found convoluted and dilated capillaries Medical Center, Rene Descartesdreef 1, PO box 9101, 6500 HB Nijmegen, in symptomless skin of psoriasis patients. Detmar et al the Netherlands. mechanistically revealed that VEGF (vascular endothelial Email: email@example.com Hanssen et al 107 capillary loops. Subsequently, epidermal turnover could be the local ethics committee and conducted according to the primary defect in the psoriatic process, while the cutaneous Declaration of Helsinki principles. microvasculature fulfills a modulator role. Included psoriasis-patients had not been on a systemic anti- Perfusion measurements of symptomless skin surrounding psoriatic drug for at least 6 weeks and all topical treatment of lesions, using laser Doppler flowmetry and speckled camera, the target lesion was stopped 2 weeks prior to the biopsy. The revealed an increased perilesional perfusion. Therefore, devel- healthy controls had no signs or (family) history of skin dis- orders; the gender, age (þ/- 2 years) and localization of the opment of new lesions could possibly be predicted by these biopsied skin were matched with that of the patient. assessments. Additional studies revealed that foci of increased In all attendees a physical assessment was performed, perfusion are associated with foci of inflammation, with including a general internal examination and inspection of the increased transcription and expression of IL-17 and Th1-cells. skin. The general physical examination involved assessment of There is evidence that hypoxia plays an essential initiating the blood pressure, a Body Mass Index-score and auscultation role in the changes in the microvasculature of inflamed skin. of the heart, considering the fact these items could potentially Hypoxia has been suggested to be relevant to the pathogenesis 10-12 affect the cutaneous vasculature. of psoriasis. Hypoxia-inducible factor-1a (HIF-1a), an Healthy volunteers were assessed to confirm that there were indicator of cellular hypoxia, is crucial in (micro)vascular indeed no skin abnormalities visible, before they got included. reshaping since it regulates angiogenesis by modulation of In the psoriasis patients a PASI (Psoriasis Area Severity Index), essential factors as fibroblast growth factor-2 (FGF-2), vascular BSA (Body Surface Area) score and a separate SUM-score endothelial growth factor-A (VEGF-A) and VEGF-receptors. (scale 0-3; mild/moderate/severe) of erythema, desquamation Overproduction of HIF-1a and target-gene VEGF induce for- and induration of the target lesion were determined. A target mation of leaky dilated vessels by, inter alia, targeting induci- psoriasis plaque was selected, based on the size (diameter 5 ble nitric-oxide synthetase, an enzyme producing nitric-oxide cm), SUM-score (SUM-score 5) and in consultation with the (NO). The exact role of HIF-1a in the pathogenesis of psoriasis patient; with regard to the possibility of scarring or occurrence is still unclear. of Koebner phenomena due to skin-biopsies. The patients had So far, the order of events in the cascade resulting in the stable chronic plaque psoriasis, with no evident history of pro- psoriatic plaque is not well understood. There is, however, gression and extension of the lesions in the last 2 weeks. some evidence that the microvasculature may be involved in In all participants biopsies were obtained after local anesthe- the early phase of development of the lesion. sia (xylocaı¨n2%/adrenaline 1:200,000). The aim of the present study is to assess the pathological In all patients four 3 mm biopsies were obtained. Two biop- involvement of capillaries in the context of well-established sies were taken from the target psoriatic plaque (ML and CL) features in the pathology of the psoriatic lesion: T-cells, neu- 9,14,15 and 2 from symptomless skin adjacent (2-3 cm) (SAL) and trophils and epidermal proliferation. These parameters distant (15 cm) (SDL) to a psoriatic lesion (including the target were evaluated in 4 consecutive phases of the development psoriatic plaque). In healthy controls one 3 mm biopsy was of the psoriatic lesion: the center of the lesion (CL) and margin performed on the same body part and visually on the exact zone of the lesion (ML) and symptomless skin adjacent to same location as where the SDL biopsy was taken in patients (SAL) and distant to (DSL) psoriatic plaques. to which they were matched (Table 1). In this study biopsies were collected from the psoriatic pla- que in the 4 phases of development. The degree of hypoxia (HIF-1a) together with various para- Immunohistochemistry meters of the vasculature including the vascular network size The biopsies were formalin-fixed, paraffin embedded and sec- (vascular area ratio (VAR), microvascular density (MVD)), the tioned at 4 mm. After deparaffinizing and rehydration of the vessel diameter and angiogenesis (proliferating endothelial tissue samples, antibody retrieval was achieved by EDTA- cells) were studied together with the well-established constitu- buffer (pH 9.0, 10 minutes at 96 C) for the Ki67/CD31 ents of the psoriatic lesion: influx of neutrophils (elastase pos- double-staining and citrate-buffer (pH 6.0, 20 minutes at itive cells), Th1-cells (T-Bet positive cells) and epidermal 96 C) for HIF-1a. All other staining did not require any anti- proliferation (Ki67þ cells). The same variables were studied body retrieval. Endogenous peroxidase activity was blocked by in skin biopsies of matched healthy controls. 3% H O in phosphate-buffered saline (PBS). Sections were 2 2 incubated with the primary antibodies dissolved in 1% bovine serum albumin (for all primary antibodies used and incubation Materials and Methods times see Table 2). In the CD31/Ki67 double-staining, the Ki67-antibody was Subjects first visualized using a peroxidase-based Envision kit Ten patients with chronic plaque psoriasis and 10 matched (DAKO, Glostrup, Denmark) 3-3 -diaminobenzidine metal- healthy controls (volunteers without psoriasis) were included enhanced (Metal-Enhanced DAB substrate-kit, Thermo Sci- in this study. Written informed consent was given by all sub- entific, US). Subsequently, the visualization of CD31 was jects before inclusion. The experiments were approved by the achieved with BrightVision (BrightVision Poly-AP anti-Ms 108 Journal of Psoriasis and Psoriatic Arthritis 6(2) Table 1. Patient Characteristics. corneum. Within the dermal compartment, the region of interest was defined as the surface from the basement mem- Psoriasis patients Healthy controls branedownto350 mm. HIF-1aþ keratinocytes were determined and expressed as Male (%) / female (%) 6 (60%) / 4 (40%) 6 (60%) / 4 (40%) Mean age (range) 45.9 (20-64) 46.6 (21-63) percentage of the total count of keratinocytes. Keratinocyte- Mean BMI (range) 25.4 (22.4-28.4) 23.3 (21.2-26.1) nuclei positive for Ki67 were described as Ki67þ cells per Blood pressure (mmHg) millimeter length of the basement membrane. T-betþ (Th1) Systolic 131.5 (106-149) 125 (100-150) and Elastaseþ (neutrophil) cells were counted and expressed Diastolic 78.2 (62-92) 81.2 (63-92) as number of positive cells per mm dermis. Biopsy localization The vasculature was evaluated using several characteristics Arm 3 3 Back 6 6 of the blood vessels and vascular bed (from the basement Leg 1 1 membrane down to 350 mm). The vascular network size was Mean PASI-score (range) 7.88 (3.5-12.9) – examined using the microvascular density (MVD) and the Mean BSA-score (range) 8 (5-15) – vascular area ratio (VAR). The MVD represents the number Mean SUM-score 7.5 (5-9) – of vessels in the selected area. The VAR is defined as the area occupied by (micro)vessel; the area stained for CD31 within Abbreviations: BMI, Body Mass Index; PASI-score, Psoriasis Area Severity Index; BSA-score, Body Surface Area. the selected area. The vessel diameter (VD) is determined as SUM-score, Erythema, desquamation and induration of the target lesion. the smallest part of a vessel-lumen (in mm) surrounded by endothelial cells (ECs). Since the vessel diameter could potentially be influenced by Table 2. Overview of the Primary Antibodies. the location of dissection of the vessel in the tissue sample, multiple tissue slices with multiple visual fields were examined Function and/or Designation and 17-19 in every biopsy in every individual. Target cell source source of antibodies Dilution Endothelial cells that double-stain CD31 (endothelial mar- CD31 Endothelial cells M0823; JC70A, Dako 1: 20 ker) and Ki67 (proliferation marker) are considered as prolif- Ki67 Epidermal or M7240; MIB-1, Dako 1: 100 erating ECs (pECs). pECs were counted and expressed as endothelial Ki67þ ECs relative to the total endothelial surface (mm ). proliferation T-Bet T helper 1 cells Sc-21003; H-210, R&D 1: 1 500 Systems Statistics Elastase Neutrophils M0752; NP57, Dako 1: 10 000 Results were expressed as mean + standard error of the mean HIF-1a Hypoxia ESEE122; AB8366, Abcam 1: 1000 (intracellular) (SEM). For the statistical analysis SPSS version 25 was used (SPSS, Benelux BV, the Netherlands). Differences in the immunohistochemical variables were assed using a Wilcoxon matched pairs signed rank test. P-values of < 0.05 were con- sidered statistically significant. IgG from ImmunoLogic, the Netherlands). HIF-1a-, T-bet- and the Elastase-antibody were stained using the same Results peroxidase-based EnVision kit and 3-3 -diaminobenzidine metal-enhanced kit as described in the Ki67-staining. All sec- Subject Characteristics tions were counterstained with Mayer’s haematoxylin (Sigma-Aldrich). Substitution with 1% PBS served as nega- In this study, 10 psoriasis patients and 10 matched healthy tive controls. controls were included. The composition of the 2 groups of volunteers, psoriasis patients and healthy matched volunteers is equal. In both groups there are 6 males and 4 females; aged 20-64 years in the psoriasis group and 21-63 years in the Quantification of Surface Area and Cells matched healthy volunteers. The characteristics of all subjects, Immunologically stained tissue samples were captured using the patients and controls, are displayed in Table 1. Mirax Midi Scanner (3DHISTECH, Budapest, Hungary). Slides were mechanically scanned with fully automated focusing and Size of the Vascular Network tissue finding, using a x20 objective lens Plan-Apochromat (Carl Zeiss, Jena, Germany), NA ¼ 0.8] and images were stored in The size of the vascular network was determined on 2 para- jpg-compression based format (3DHistech) and set to an 80% meters: the vascular area ratio (VAR) and the micro-vascular compression ratio (pixel size 0.23 mm). density (MVD). Processing package Fiji 1.47 was used to evaluate all The MVD, the number of blood vessels in the selected area tissue samples. Regarding the epidermis an area across the of the skin in healthy volunteers and in SDL of psoriasis whole section was measured, excluding the stratum patients did not differ from each other (30.7 + 1.5 vs Hanssen et al 109 Figure 1. Overview of immunohistological results. A, Micro vascular density (MVD): the number of (micro)vessels in the selected area of the dermis (per mm ). B, Vascular Area Ratio (VAR): fraction of the area occupied by (micro)vessel within the selected dermal area (in %). C, Vessel diameter: the smallest part of vessel-lumen (in mm). D, Endothelial Cell Proliferation (Ki67þ EC nuclei per CD31þ mm ). E, Ki67þ kerati- nocytes per mm length of basement membrane. F, T-BET: the number of Th1-cells expressed as the number of positive cells per mm dermis. G, Elastase: the number of neutrophils expressed as the number of positive cells per mm dermis. H, HIF-1a: HIF-1a þ keratinocytes (in %). The Bar charts represent the results of the analyzed skin biopsies including the psoriatic lesion, the symptomless skin and the skin of matched healthy controls. The psoriatic lesion includes the center of the lesion (CL), margin of the lesion (ML), the symptomless skin adjacent to the lesion (SAL), the symptomless skin distant to the lesion (SDL). Matched healthy controls (HC). Means + SEM. *p < 0.05: statistically significant compared to skin of the matched healthy controls. * : Statistically significant compared to 2 subsequent biopsies. 2 2 33.8 + 1.6 vessels/mm ;p ¼ 0.24) (Figure 1). The volunteers (3.6 + 3.7 pECs/CD31 mm ;p ¼ 0.32). The level MVD expanded considerable and significantly in SAL of proliferating ECs expanded to nearly significant in SAL 2 2 (43.3 + 3 vessels/mm ;p ¼ 0.02) and extended even further (35 + 18 pECs/CD31 mm ;p ¼ 0.10). In the psoriatic plaques in the psoriatic plaque (ML and CL (77.0 + 3.8 and the rise becomes substantial (ML: 138.7 + 25 and CL: 2 2 81.4 + 5 vessels/mm ; both P < 0.01) (Figures 1 and 2). 116 + 22 pECs/CD31 mm ; p < 0.05). The VAR, the area fraction of ECs in a selected tissue area, was 2.3 + 0.3% in the skin of healthy volunteers. The VAR in HIF-1a Levels SDL revealed similar results (2.6 + 0.3%;p ¼ 0.21). In SAL, a HIF-1a expression is limited and quite similar in SDL com- small but significant increase (3.0 + 0.2%;p ¼ 0.01) was pared to skin of healthy volunteers (in both groups: 0.7% + 0.2 observed. The VAR in the psoriatic plaques itself (ML and of the total number of keratinocytes; p ¼ 0.8). CL) is evidently increased. HIF-1a expression is evidently increased in SAL (1.2% + 0.2; p ¼ 0.04) and within the psoriatic plaque (ML: 12.4% + Vessel Diameter (VD) 0.8; CL: 10.9% + 0.7; both p < 0.01%). A substantial expan- The mean diameter of the vessel lumen (VD), the smallest part sion in HIF-1a is noticed comparing the results of SAL to SDL. of the vessel-lumen (in mm) surrounded by endothelial cells (ECs), in healthy skin is 7.0 + 0.3 mm. Results demonstrated Inflammatory Cells: T-Bet / Elastase an increased VD in all psoriatic skin (lesional and symptomless Regarding the T-Betþ Th1-cell subset, the number is similar skin) compared to healthy skin (SDL: 8.1 + 0.4 mm; p ¼ < in SDL compared to healthy skin (22.7 + 1.7 vs 20.4 + 1.4; 0.05; SAL 11.6: + 0.6 mm, ML: 12.3 + 0.5 mm, CL: 14.7 + p ¼ 0.2). In the psoriatic plaque a firm higher average is 0.4 mm; in SAL, ML and CL: p < 0.05) (Figure 1, Table 3). observed, with a maximum number of cells detected in the center of the psoriatic plaque (CL: 170.7 + 9.0). The number Proliferating Endothelial Cells (pECs) of Th1-cells increases significantly in each of the subsequent In healthy skin proliferating Endothelial Cells (pEC) are almost biopsies; the closer to the center of the psoriasis plaque the non-existent (0 + 0.0 pECs/CD31 mm ). Although an increase biopsy was taken, the higher the amount of T-Betþ cells. in the number of proliferating ECs is found in the SDL, these The influx of elastaseþ neutrophils is augmented in all results do not significantly differ from the skin of healthy psoriatic skin sites compared to healthy skin. In 110 Journal of Psoriasis and Psoriatic Arthritis 6(2) SDL the increase of the number of neutrophils is small, but statistically significantly different from healthy skin (p ¼ 0.02). SAL reveals a tendency of a mild, significant, increase in neu- trophils (SAL: 32.8 + 2.5 versus SDL: 9.9 + 1.6; p ¼ 0.01) (Figure 3). However, a very significant surge of elastaseþ neutrophils is observed in the clinically affected skin ML: 113.2 + 4 and CL: 159 + 7; p < 0.01). Ki67þ keratinocyte Nuclei SDL reveals an approximately equivalent number of prolifer- ating keratinocytes compared to healthy skin; in both groups + 20 Ki67þ keratinocytes per mm basement membrane were found (p ¼ 0.8). In the psoriatic plaque the Ki67þ keratinocytes were evi- dently increased (ML: 113 + 4.0; CL: 159 + 7.1 (in both p < 0.01)). However, an increase in proliferating keratinocytes is already present in the SAL (33.0 + 2.6; p < 0.01) (Figure 1). Discussion In the present study, a statistically significant increase of the vascular diameter in all psoriatic skin sites including the SDL was observed. This result is in line with the findings of Kulka, who described the finding of dilated capillaries in symptomless psoriasis skin. Furthermore, already in SDL a statistically significant influx of neutrophils is observed; the other parameters including the hypoxia did not show statistically significant differences between the SDL and skin of normal volunteers. In symptomless skin more adjacent to a lesion (SAL) other parameters significantly increased as a concerted appearance, including vascular network size (microvascular density (MVD) and microvascular area ratio (VAR)), keratinocyte proliferation and influx of T-Betþ Th1-cells. This is consis- tent with Hendriks et al who also observed an increase in 8,9 vasculature in the SAL. These changes appear also to be associated with increased oxygen consumption, given the increase of the HIF-1a expression (a marker for hypoxia). Within the psoriatic plaque itself (ML and CL) the proliferat- ing endothelial cells significantly increase. In the selection of immune markers we decided to have T-bet as a marker for acquired immunity and neutrophils as a marker for innate immunity. We have studied these mar- 17,18 kers in several inflammatory conditions. However, Th17 is generally considered a more important T-cell in the pathogenesis of psoriasis. Therefore, in future studies on psoriasis we will evaluate Th17 cells (ROR-gt) in combina- tion with IL-17 and -23 as these cytokines drive the immune pathogenesis of psoriasis. In summary, in symptomless psoriatic skin distant from a psoriasis plaque, activation of the innate immune system, wit- Figure 2. Representative photographs of the CD31/Ki67 double- nessed by neutrophil increases and subclinical vasodilatation staining in the psoriatic skin. The psoriatic lesion includes the center of can be recorded. the lesion (CL), margin of the lesion (ML), the symptomless skin Closer to the psoriatic plaque, which is more downstream in adjacent to the lesion (SAL), the symptomless skin distant to the lesion the psoriatic pathogenesis, vascular and epithelial proliferation (SDL). Matched healthy controls (HC). Hanssen et al 111 Table 3. Vessel Diameter (VD) in Biopsies in Psoriasis Patients Versus Biopsy of Matched Healthy Control per Body Location. p-value Location of biopsy HC SDL SAL ML CL HC vs SDL Arm 7.4 + 0.4 9.0 + 0.9 12.0 + 1.3 13.9 + 0.7 15.9 + 0.6 P ¼ 0.20 Back 6.7 + 0.3 7.7 + 0.4 11.4 + 0.6 11.5 + 0.5 14.2 + 0.4 P ¼ 0.07 Leg 5.9 + 0.4 7.9 + 1 12.4 + 0.6 11.2 + 0.3 15.6 + 0.8 P ¼ 0.28 Total 7.0 + 0.3 8.1 + 0.4 11.6 + 0.6 12.3 + 0.5 14.7 + 0.4 P < 0.05 The mean vessel diameter (VD) of all biopsies in biopsies performed in psoriatic patients and their healthy matched controls. Biopsies in the psoriatic patients include the SDL (symptomless skin 15 cm distant form the target psoriatic plaque), SAL (symptomless skin 2-3 cm from the target psoriatic lesion), ML (margin of the psoriatic plaque) and CL (center of the psoriatic lesion). In the healthy matched control (HC) the biopsy was taken at visually the exact same location on the same body part as the SDL in the matched psoriatic patient. Results are presented as mean + standard error of mean. Wilcoxon matched pairs signed rank test. P-values of < 0.05 were considered statistically significant. Figure 3. Representative photographs Elastase-staining SDL versus HC. Representative photographs of the Elastase-staining in symptomless psoriatic skin 15 cm distant from a psoriatic lesion (SDL) in 2 patients and in the 2 matched healthy controls (HC). These biopsies were performed on visually the exact same location and same body part in the psoriatic patients and their matched healthy controls. are recorded, along with HIF-1a (hypoxic) cells and activation Declaration of Conflicting Interests of the acquired immunity witnessed by T-Bet cells. The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Van der Vleuten CJM is involved as a medical consultant at Authors’ Note Pierre Fabre. Seyger MMB received grants from/was involved in clin- The experiments were approved by the local ethics committee and ical trials from Abbvie, Almirall, Astellas, Janssen, Leo Pharma, Lilly conducted according to the Declaration of Helsinki principles. Written and Pfizer. She served as a consultant for Abbvie, Admirall, Boehrin- informed consent was given by all subjects before inclusion. ger Ingelheim, Janssen, Lilly and Pfizer. She gave lectures for Abbvie, Janssen, Lilly and Pfizer and traveled with Abbvie, Lily, Pfizer and Acknowledgments Leo Pharma to meetings; fees were paid directly to the institution. Van de Kerkhof PCM has carried out consultancy services for Celgene, The authors would like to thank all volunteers who participated in this Centocor, Almirall, Amgen, Pfizer, Philips, Abbott, Eli Lilly, Gal- study and I. Otte-Holler and U. Flucke for their valuable contribution derma, Novartis, Janssen Cilag, Leo Pharma, Sandoz, Mitsubishi, to the immunohistochemical procedures during this project. 112 Journal of Psoriasis and Psoriatic Arthritis 6(2) Sandoz. He carried out clinical trials for Basilea, Pfizer, Eli Lily, 9. Hendriks AG, Steenbergen W, Zeeuwen PL, et al. Perfusion Amgen, Abbvie, Philips Lighting, Janssen Cilag and Leo Pharma. intensity correlates with expression levels of psoriasis-related genes and proteins. Skin Pharmacol Physiol. 2015;28(6):296-306. Funding 10. 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Journal of Psoriasis and Psoriatic Arthritis – SAGE
Published: Apr 1, 2021
Keywords: vasculature; angiogenesis; psoriasis; hypoxia; inflammation
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