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

类风湿性关节炎（RA）是一种以滑膜微血管扩张为特征的慢性炎症性关节疾病 作为疾病进展的特征。滑膜新血管形成需要细胞增殖， 存在的血管内皮细胞（EC），或从内皮前体细胞（EPCs）募集 分化为EC。EC招募和分化由一系列事件精心策划，包括 血管腔表达粘附分子，捕获循环EPCs，然后分化为 成熟EC。趋化因子肯定参与了这一过程，有人认为趋化因子 可能通过抑制EC凋亡、减少EC更新和促进血管生成而发挥作用 增长这将导致RA关节的细胞募集增加， 应答因此，了解EC募集和凋亡对于发展 治疗类风湿性关节炎已经确定EPCs分化为各种成熟细胞类型， 而分化的EC可来源于其它祖细胞。然而，目前还不清楚如何以及何时 内皮祖细胞在体内分化为不同的细胞。因此，观察非定向干细胞带来了问题， 当研究它们在体内新血管形成和血管生成中的作用时。此外， 关于分化或未分化EC对滑膜新血管形成的相对贡献， 发生在RA。本研究将阐明内皮细胞是如何被募集到RA滑膜中的，并将确定在何种程度上 趋化因子介导该过程并增强血管生长。我们建议调查的假设 分化的真皮人微血管内皮细胞（HMVECs），以及未分化的EC 类似地被募集到RA滑膜中的新血管形成部位，其中它们掺入到 血管壁作为功能性内皮。具体来说，我们将比较分化和未分化的EC 招募正常（NL）和RA滑膜组织（ST）移植到严重的联合免疫缺陷 （SCID）小鼠嵌合体。利用这个模型，我们将研究介导EC募集的趋化因子， 启动血管形成，并在体内介导EC抗凋亡活性。总的来说，这项研究的结果将 提供了一种相对简单的方法来检查体内EC募集，并提供了一种合适的替代方法， 研究RA相关动物模型中血管生成、EC趋化性和细胞凋亡。

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.