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