Abstract
IntroductionAngiogenesis is an early event in the pathogenesis of both psoriatic arthritis (PsA) and rheumatoid arthritis (RA); however, there are striking differences in blood vessel morphology and activation between the two arthropathies. The aim of this study was to assess if the PsA and RA joint microenvironments differentially regulate endothelial cell function.MethodsPsA and RA primary synovial fibroblasts (SFC) were isolated from synovial biopsies, grown to confluence, and supernatants harvested and termed ‘conditioned media’ (CM). Human umbilical vein endothelial cells (HUVEC) were cultured with PsA SFC or RA SFC-CM (20%). HUVEC tube formation, migration, and PBMC adhesion were assessed by matrigel tube formation, wound repair, and PBMC adhesion assays. HUVEC cell surface expression of ICAM, VCAM, and E-Selectin was assessed by flow cytometry. Transcriptome analysis of genes promoting angiogenesis was performed by real-time PCR. Finally, a MSD multiplex angiogenic assay was performed on PsA SFC and RA SFC supernatants.ResultsMacroscopic synovitis and vascularity were similar in PsA and RA patients; however, significant differences in vascular morphological pattern were recorded with tortuous, elongated vessels observed in PsA compared to straight regular branching vessels observed in RA. Transcriptome analysis showed strong upregulation of the pro-angiogenic signature in HUVEC primed with PsA SFC-CM compared to RA SFC-CM and basal control. In parallel, paired PsA SFC-CM significantly induced HUVEC tube formation compared to that of RA SFC-CM. Furthermore, PsA SFC-CM induced HUVEC migration was paralleled by a significant induction in VEGFA, PFKFB3, ICAM-1, and MMP3 mRNA expression. A significant increase in PBMC adhesion and cell surface expression of VCAM-1, ICAM-1, and E-Selectin expression was also demonstrated in PsA SFC-CM-primed HUVEC compared to RA SFC-CM. Finally, VEGF, TSLP, Flt-1, and Tie-2 expression was elevated in PsA SFC-CM compared to RA SFC-CM, with no significant difference in other pro-angiogenic mediators including MIP-3, bFGF, PIGF, and MCP-1.ConclusionPsA SFC and RA SFC secreted factors differentially regulate endothelial cell function, with soluble mediators in the PsA joint microenvironment inducing a more pro-angiogenic phenotype compared to the RA.
Highlights
Angiogenesis is an early event in the pathogenesis of both psoriatic arthritis (PsA) and rheumatoid arthritis (RA); there are striking differences in blood vessel morphology and activation between the two arthropathies
The pro-angiogenic transcriptome of PsA and RA Synovial fibroblast cells (SFC)-CMprimed Human umbilical vein endothelial cells (HUVEC) are divergent Previous studies have demonstrated distinct synovial vascular morphology in PsA compared to RA; the underlying mechanisms involved are still unclear [2, 4]
We further investigated whether the RA and PsA joint microenvironment contributes to the observed distinct vascular patterns
Summary
Angiogenesis is an early event in the pathogenesis of both psoriatic arthritis (PsA) and rheumatoid arthritis (RA); there are striking differences in blood vessel morphology and activation between the two arthropathies. An increase in blood vessel number has been demonstrated by many studies [4,5,6], which may be due to the elongation and increased tortuosity of existing vessels, rather than an increase in the actual number of new vessels These changes are associated with differential circulatory and synovial expression of angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang2), placental growth factors (PIGF), and stromal derived growth factor-1 (SDF-1), in addition to cytokines and matrix metalloproteinases (MMPs) [1, 6,7,8,9,10]. Increased expression of these growth factors has been demonstrated in early PsA synovial membrane compared to RA [7, 9, 11], suggesting that mechanisms involved in regulating the distinct vascular morphology in PsA occur at an early stage of disease
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