Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with microvascular expansion in synoviumas a characteristic feature of disease progression. Synovial neovascularization requires either proliferation ofexistent 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 includingvessel lumen expression of adhesion molecules that capture circulating EPCs, followed by differentiation intomature ECs. Chemokines are certainly involved in this process, and it has been suggested that chemokinesmay play a role in angiogenesis by inhibiting EC apoptosis, decreasing EC turnover and favoring vesselgrowth. This would result in increased cell recruitment to the RA joint and exacerbate inflammatoryresponses. Therefore, understanding EC recruitment and apoptosis are critical for development oftherapeutics 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 whenEPCs differentiate into different cells in vivo. Thus, looking at non-committed stem cells poses problemswhen studying their role in neovascularization and angiogenesis in vivo. In addition, little information existsregarding the relative contribution of differentiated or undifferentiated ECs to synovial neovascularization thatoccurs in RA. This study will clarify how ECs are recruited to RA synovium and will determine to what extentchemokines mediate this process and enhance vessel growth. We propose to investigate the hypothesisthat differentiated dermal human microvascular endothelial cells (HMVECs), as well as undifferentiated ECsare similarly recruited to sites of neovascularization in the RA synovium, wherein they incorporate into thevascular wall as functional endothelium. Specifically, we will compare differentiated and undifferentiated ECrecruitment 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 willprovide a relatively simple method to examine EC recruitment in vivo, and provide a suitable alternative toinvestigate angiogenesis, EC chemotaxis, and apoptosis in a relevant animal model of RA.
Showing the most recent 10 out of 88 publications
