P1: Vascular Endothelial Cells Recruitment, RA Synovium, Chemotaxis Angiogenesis

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with microvascular expansion in synovium[unreadable] as a characteristic feature of disease progression. Synovial neovascularization requires either proliferation of[unreadable] existent vascular endothelial cells (ECs), or recruitment from endothelial precursor cells (EPCs)[unreadable] differentiating into ECs. EC recruitment and differentiation are orchestrated by a series of events including[unreadable] vessel lumen expression of adhesion molecules that capture circulating EPCs, followed by differentiation into[unreadable] mature ECs. Chemokines are certainly involved in this process, and it has been suggested that chemokines[unreadable] may play a role in angiogenesis by inhibiting EC apoptosis, decreasing EC turnover and favoring vessel[unreadable] growth. This would result in increased cell recruitment to the RA joint and exacerbate inflammatory[unreadable] responses. Therefore, understanding EC recruitment and apoptosis are critical for development of[unreadable] therapeutics to combat RA. It is well established that EPCs differentiate into various mature cell types,[unreadable] whereas differentiated ECs can be derived from other progenitor cells. However, it is unclear how and when[unreadable] EPCs differentiate into different cells in vivo. Thus, looking at non-committed stem cells poses problems[unreadable] when studying their role in neovascularization and angiogenesis in vivo. In addition, little information exists[unreadable] regarding the relative contribution of differentiated or undifferentiated ECs to synovial neovascularization that[unreadable] occurs in RA. This study will clarify how ECs are recruited to RA synovium and will determine to what extent[unreadable] chemokines mediate this process and enhance vessel growth. We propose to investigate the hypothesis[unreadable] that differentiated dermal human microvascular endothelial cells (HMVECs), as well as undifferentiated ECs[unreadable] are similarly recruited to sites of neovascularization in the RA synovium, wherein they incorporate into the[unreadable] vascular wall as functional endothelium. Specifically, we will compare differentiated and undifferentiated EC[unreadable] recruitment to normal (NL) and RA synovial tissue (ST) engrafted in a severe combined immunodeficient[unreadable] (SCID) mouse chimera. With this model, we will investigate the chemokines that mediate EC recruitment,[unreadable] initiate vessel formation, and mediate EC anti-apoptotic activity in vivo. Overall, the results of this study will[unreadable] provide a relatively simple method to examine EC recruitment in vivo, and provide a suitable alternative to[unreadable] investigate angiogenesis, EC chemotaxis, and apoptosis in a relevant animal model of RA.