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From the Departments of Pathology*
and
Pharmacology,
Boyer Center for Molecular
Medicine, Yale University School of Medicine, New Haven, Connecticut;
and ISIS Pharmaceuticals,
Carlsbad, California
The protective genes that mediate endothelial cell (EC)
survival during angiogenesis have not been completely characterized.
Here, we show that an antisense oligonucleotide to the
apoptosis inhibitor survivin suppressed de novo
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 assays, antisense
targeting of survivin abolished the anti-apoptotic function of VEGF
against tumor necrosis factor-
- or ceramide-induced cell
death, enhanced caspase-3 activity, promoted the
generation of a 
17-kd active caspase-3 subunit, and
increased cleavage of the caspase substrate, polyADP ribose
polymerase. In contrast, the survivin antisense oligonucleotide
had no effect on EC viability in the absence of VEGF. Antisense
oligonucleotides to platelet-endothelial cell adhesion molecule-1
(PECAM-1, CD31), lymphocyte function-associated
molecule-3 (LFA-3, CD58), or intercellular adhesion
molecule-1 (ICAM-1, CD54) did not reduce the anti-apoptotic
function of VEGF in endothelium. When tested on other angiogenic
activities mediated by VEGF, survivin antisense treatment
induced rapid regression of three-dimensional vascular capillary
networks, but did not affect EC migration/chemotaxis. These
data suggest that the anti-apoptotic properties of VEGF during
angiogenesis are primarily mediated by the induced expression of
survivin in ECs. Manipulation of this pathway may increase EC viability
in compensatory angiogenesis or facilitate EC apoptosis and promote
vascular regression during tumor angiogenesis.
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