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建，最终导致血管狭窄。最近发现，促进血管内皮细胞存活的机制在血管生成过程中也是必不可少的。我们已经证明，骨桥蛋白，一个αvbeta3的配体，在血管生成/再生的内皮细胞中被协同诱导，并能促进内皮细胞的存活。因此，在血管生成过程中，内皮细胞可能需要增强的保护机制，以共同调节细胞之间以及与细胞外基质之间改变的黏附相互作用。在炎症条件下，这可能特别重要，以防止有害的炎症介质导致的过早死亡。我们的初步数据表明，这些保护机制中至少有一个涉及α-β3介导的选择性诱导NfkappaB，以及随后诱导的可溶性肿瘤坏死因子受体家族成员--护骨素。本文提出的研究旨在通过以下几个方面来验证这一假说：1)表征由αvbeta3启动的依赖于NfkappaB活性的内皮细胞存活的新的信号通路；2)确定NfkappaB诱导的基因--骨保护素在内皮细胞存活中的作用；以及3)确定NfkappaB和骨整合蛋白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.