Survivin-dependent angiogenesis in ischemic brain: molecular mechanisms of hypoxia-induced up-regulation.
Approaches to regulating angiogenesis in the brain, which may diminish parenchymal damage after stroke, are lacking. Survivin, the inhibitor of apoptosis protein, is up-regulated in vitro in vascular endothelial cells by angiogenic factors, including vascular endothelial cell growth factor (VEGF). To evaluate the in vivo role of survivin in the brain in response to hypoxia/ischemia, we used a mouse model of stroke and show that 2 days after permanent middle cerebral artery occlusion, survivin is uniquely expressed by microvessels that form in the peri-infarct and infarct regions. The extent of vascularization of the infarct is dependent on expression of survivin, since vessel density is significantly reduced in mice with heterozygous deficiency of the survivin gene (survivin+/- mice), even though infarct sizes were not different. Hypoxia alone induces survivin expression in the brain, by cultured endothelial cells and by embryonic stem cells, but this response is at least partially independent of VEGF, hypoxia inducible factor 1alpha, or placental growth factor. Delineating the spatiotemporal pattern of expression of survivin after stroke, and the molecular mechanisms by which this is regulated, may provide novel approaches to therapeutically optimize angiogenesis in a variety of ischemic disorders.
Conway
Edward M
EM
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Gasthuisberg O&N, 9th Floor, Herestraat 49, B-3000 Leuven, Belgium. ed.conway@med.kuleuven.ac.be
Zwerts
Femke
F
Van Eygen
Veerle
V
DeVriese
Astrid
A
Nagai
Nobuo
N
Luo
Wei
W
Collen
Désiré
D
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D001808:Blood Vessels / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D002545:Brain Ischemia / Q000150:complications / Q000209:etiology / Q000503:physiopathology*; D002478:Cells, Cultured; D002536:Cerebral Arteries; D016228:Endothelial Growth Factors / Q000378:metabolism; D002534:Hypoxia, Brain / Q000209:etiology / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins; D018919:Neovascularization, Physiologic; D010100:Oxygen / Q000378:metabolism; D000077022:Survivin; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C107489:BIRC5 protein, human; D016228:Endothelial Growth Factors; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D010100:Oxygen