Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting.
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-alpha- or ceramide-induced cell death, enhanced caspase-3 activity, promoted the generation of a approximately 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.
Mesri
M
M
Department of Pathology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Morales-Ruiz
M
M
Ackermann
E J
EJ
Bennett
C F
CF
Pober
J S
JS
Sessa
W C
WC
Altieri
D C
DC
D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D016373:DNA, Antisense / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C107489:BIRC5 protein, human; D016373:DNA, Antisense; D016228:Endothelial Growth Factors; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA