Numerous studies have shown that SFC secrete multiple soluble angiogenic growth factors including VEGF, angiopoietins, basic fibroblast growth factor (bFGF), and MMP2/9. In conjunction with this, fibroblasts are also thought to play a key role in angiogenesis. SFC interact with the cells within the inflamed synovium through the secretion of multiple pro-inflammatory factors that regulate their pathologic activities. Synovial fibroblast cells (SFC) are a crucial cell population in the inflamed synovium microenvironment and promote the initiation and progression of joint destruction, immune cell invasion, and angiogenesis. The synovial microenvironment, which is composed of stromal cells, immune cells, endothelial cells, and extracellular matrix components, plays an important role in disease progression in inflammatory arthritis. Increased expression of these growth factors has been demonstrated in early PsA synovial membrane compared to RA, suggesting that mechanisms involved in regulating the distinct vascular morphology in PsA occur at an early stage of disease. 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). At a microscopic level, an increase in blood vessel number has also been demonstrated by many studies, which may be due to the elongation and increased tortuosity of existing vessels, rather than an increase in the actual number of new vessels. While the observed tortuous vascular pattern in PsA is a consistent finding, studies have shown in RA that rheumatoid factor (RF) positivity is associated with the regular straight vascular pattern, while RA RF negative patients can display a tortuous pattern. PsA synovial vasculature is characterised as elongated, tortuous vessels with minimal branching, while RA synovia display straight, regular branching vessels. We and others have previously demonstrated distinct macroscopic vascular morphology in the joints of inflammatory arthritis. 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.ĭysregulated angiogenesis is an early event in inflammatory arthritis (IA), facilitating leukocyte recruitment and synovial membrane hyperplasia and creating an aggressive pannus tissue capable of destroying adjacent cartilage and bone.
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.
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. Furthermore, PsA SFC-CM induced HUVEC migration was paralleled by a significant induction in VEGFA, PFKFB3, ICAM-1, and MMP3 mRNA expression. In parallel, paired PsA SFC-CM significantly induced HUVEC tube formation compared to that of RA SFC-CM. 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. 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. Finally, a MSD multiplex angiogenic assay was performed on PsA SFC and RA SFC supernatants. Transcriptome analysis of genes promoting angiogenesis was performed by real-time PCR. HUVEC cell surface expression of ICAM, VCAM, and E-Selectin was assessed by flow cytometry. HUVEC tube formation, migration, and PBMC adhesion were assessed by matrigel tube formation, wound repair, and PBMC adhesion assays. Human umbilical vein endothelial cells (HUVEC) were cultured with PsA SFC or RA SFC-CM (20%).
PsA and RA primary synovial fibroblasts (SFC) were isolated from synovial biopsies, grown to confluence, and supernatants harvested and termed ‘conditioned media’ (CM). The aim of this study was to assess if the PsA and RA joint microenvironments differentially regulate endothelial cell function. 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.
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