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.
Showing the most recent 10 out of 632 publications
