Control of apoptosis during angiogenesis by survivin expression in endothelial cells.
Mechanisms controlling endothelial cell survival during angiogenesis were investigated. Stimulation of quiescent endothelial cells with mitogens, including vascular endothelial growth factor and basic fibroblast growth factor, induced up to approximately 16-fold up-regulation of the cell cycle-regulated apoptosis inhibitor survivin. Mitogen stimulation rapidly increased survivin RNA expression in endothelial cells, which peaked after 6 to 10 hours in culture and decreased by 24 hours. Inflammatory cytokines, tumor necrosis factor alpha, and interleukin-1 did not induce survivin expression in endothelial cells. Formation of three-dimensional vascular tubes in vitro was associated with strong induction of survivin in endothelial cells, as compared with two-dimensional cultures. By immunohistochemistry, survivin was minimally expressed in endothelium of nonproliferating capillaries of normal skin, whereas it became massively up-regulated in newly formed blood vessels of granulation tissue in vivo. Recombinant expression of green fluorescent protein survivin in endothelial cells reduced caspase-3 activity and counteracted apoptosis induced by tumor necrosis factor alpha/cycloheximide. These findings identify survivin as a novel growth factor-inducible protective gene expressed by endothelial cells during angiogenesis. Therapeutic manipulation of survivin expression and function in endothelium may influence compensatory or pathological (tumor) angiogenesis.
O'Connor
D S
DS
Boyer Center for Molecular Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Schechner
J S
JS
Adida
C
C
Mesri
M
M
Rothermel
A L
AL
Li
F
F
Nath
A K
AK
Pober
J S
JS
Altieri
D C
DC
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines / Q000494:pharmacology; D008869:Microtubule-Associated Proteins; D008934:Mitogens / Q000494:pharmacology; D009363:Neoplasm Proteins; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C107489:BIRC5 protein, human; D016228:Endothelial Growth Factors; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines; D008869:Microtubule-Associated Proteins; D008934:Mitogens; D009363:Neoplasm Proteins; D011506:Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2