INTEGRIN CONTROL OF ENDOTHELIAL SURVIVAL

血管生成是动脉粥样硬化和再狭窄斑块的重要组成部分，有助于这些病变的伤口愈合，并可能有助于血管重塑，最终导致血管狭窄。最近变得明显的是，在血管生成过程中，促进内皮细胞存活的机制的上调也是必不可少的。我们已经表明，骨桥蛋白，α v β 3的配体，在血管生成/再生内皮细胞中协同诱导，并可促进内皮细胞存活。因此，假设内皮细胞可能需要增强的保护机制来保护血管生成过程中细胞之间以及与细胞外基质之间改变的粘附相互作用。这在炎症条件下可能特别重要，以防止有害炎症介质引起的过早死亡。我们的初步数据表明，这些保护机制中至少有一个涉及选择性α v β 3介导的NfkappaB诱导，以及随后的可溶性TNF受体家族成员骨保护素诱导。本文提出的研究旨在通过以下方式验证这一假设：1）表征由α v β 3启动并依赖于NfkappaB活性的内皮细胞存活的新型信号传导途径，2）鉴定NfkappaB诱导型基因骨保护素在内皮细胞存活中的作用，3）确定NfkappaB和骨保护素在体外和体内血管生成过程中的潜在作用。

Angiogenesis is a prominent component of atherosclerotic and restenotic plaques, contributing to wound healing in these lesions and likely to contribute to vascular remodeling and ultimately to vessel narrowing. It has recently become apparent that up-regulation of mechanisms which promote endothelial survival are also essential during angiogenesis. We have shown that osteopontin, a ligand for alphavbeta3, is coordinately induced in angiogenic/regenerating endothelial cells, and can promote endothelial survival. Thus it is hypothesized that endothelial cells may require enhanced protective mechanisms to copensat4e for altered adhesive interactions between cells and with the extracellular matrix during angiogenesis. This may be particularly important under inflammatory conditions to prevent premature demise caused by noxious inflammatory mediators. Our preliminary data suggest that a least one of these protective mechanisms involves selective alphavbeta3-mediated induction of NfkappaB, and subsequent induction of the soluble TNF receptor family member, osteoprotegerin. The studies proposed here are aimed at testing this hypothesis by 1) characterizing the novel signaling pathway of endothelial cell survival initiated by alphavbeta3 and dependent on NfkappaB activity, 2) identifying the role of the NfkappaB- inducible gene, osteoprotegerin, in endothelial survival, and 3) determining the potential roles of NfkappaB and osteoprotegrin in angiogenic processes in vitro and in vivo.