Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting

The protective genes that mediate endothelial cell (EC) survival during ang iogenesis have not been completely characterized. Here, me show that an ant isense oligonucleotide to the apoptosis inhibitor survivin suppressed de no vo expression of survivin in ECs by vascular endothelial cell growth factor (VEGF). in contrast, the survivin antisense oligonucleotide did not affect anti-apoptotic bcl-2 levels in endothelium. When assessed in cell death as says, antisense targeting of survivin abolished the anti-apoptotic function of VEGF against tumor necrosis factor-alpha- or ceramide-induced cell deat h, enhanced caspase-3 activity, promoted the generation of a similar to 17- kd active caspase-3 subunit, and increased clear age of the caspase substra te, polyADP ribose polymerase, in contrast, the survivin antisense oligonuc leotide had no effect on EC viability in the absence of VEGF. Antisense oli gonucleotides to platelet-endothelial cell adhesion molecule-1 (PECAM-1, CD 31), lymphocyte function-associated molecule-3 (LFA-3, CD58), or intercellu lar adhesion molecule-1 (ICAM-1, CD54) did not reduce the anti-apoptotic fu nction of VEGF in endothelium. When tested on other angiogenic activities m ediated by VEGF, survivin antisense treatment induced rapid regression of t hree-dimensional vascular capillary networks, but did not affect EC migrati on/chemotaxis. These data suggest that the anti-apoptotic properties of VEG F during angiogenesis are primarily mediated by the induced expression of s urvivin in ECs, Manipulation of this pathway may increase EC viability in c ompensatory angiogenesis or facilitate EC apoptosis and promote vascular re gression during tumor angiogenesis.