Angiogenesis 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. PsA 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. Macroscopic 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. PsA 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.

中文翻译：

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与类风湿性关节炎相比，对银屑病性关节炎滑膜的成纤维细胞有增强的血管生成功能

血管生成是银屑病关节炎（PsA）和类风湿关节炎（RA）发病机理中的早期事件。然而，两种关节病之间在血管形态和激活方面存在显着差异。这项研究的目的是评估PsA和RA关节微环境是否差异调节内皮细胞功能。从滑膜活检组织中分离出PsA和RA原发性滑膜成纤维细胞（SFC），使其生长至汇合，并收集上清液并称为“条件培养基”（CM）。用PsA SFC或RA SFC-CM（20％）培养人脐静脉内皮细胞（HUVEC）。通过基质胶管形成，伤口修复和PBMC粘附分析评估了HUVEC管的形成，迁移和PBMC粘附。通过流式细胞术评估了ICAM，VCAM和E-选择素的HUVEC细胞表面表达。通过实时PCR对促进血管生成的基因进行转录组分析。最后，对PsA SFC和RA SFC上清液进行MSD多重血管生成测定。PsA和RA患者的肉眼可见的滑膜炎和血管相似。然而，与在RA中观察到的直的规则分支血管相比，在PsA中观察到的曲折，细长的血管记录了血管形态学模式的显着差异。转录组分析显示，与RA SFC-CM和基础对照相比，以PsA SFC-CM引发的HUVEC中促血管生成的信号强烈上调。平行地，与RA SFC-CM相比，配对的PsA SFC-CM显着诱导了HUVEC管的形成。此外，PsA SFC-CM诱导的HUVEC迁移与VEGFA，PFKFB3，ICAM-1和MMP3 mRNA表达的显着诱导平行。与RA SFC-CM相比，在PsA SFC-CM引发的HUVEC中还证明了PBMC粘附力和VCAM-1，ICAM-1和E-选择素表达的细胞表面表达显着增加。最后，与RA SFC-CM相比，PsA SFC-CM中的VEGF，TSLP，Flt-1和Tie-2表达升高，在包括MIP-3，bFGF，PIGF和MCP在内的其他促血管生成介质中无显着差异。 -1。PsA SFC和RA SFC分泌的因子差异性调节内皮细胞功能，与RA相比，PsA关节微环境中的可溶性介导物诱导了更多促血管生成的表型。与RA SFC-CM相比，PsA SFC-CM中Tie-2表达升高，而在其他促血管生成介质（包括MIP-3，bFGF，PIGF和MCP-1）中无显着差异。PsA SFC和RA SFC分泌的因子差异性调节内皮细胞功能，与RA相比，PsA关节微环境中的可溶性介导物诱导了更多促血管生成的表型。与RA SFC-CM相比，PsA SFC-CM中Tie-2表达升高，而在其他促血管生成介质（包括MIP-3，bFGF，PIGF和MCP-1）中无显着差异。PsA SFC和RA SFC分泌的因子差异性调节内皮细胞功能，与RA相比，PsA关节微环境中的可溶性介导物诱导了更多促血管生成的表型。