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(American Journal of Pathology. 2003;163:935-946.)
© 2003 American Society for Investigative Pathology

Survivin-Dependent Angiogenesis in Ischemic Brain

Molecular Mechanisms of Hypoxia-Induced Up-Regulation

Edward M. Conway^*, Femke Zwerts^*, Veerle Van Eygen^*, Astrid DeVriese^*, Nobuo Nagai, Wei Luo^* and Désiré Collen^*

From the Center for Transgene Technology and Gene Therapy,^*Flanders Interuniversity Institute for Biotechnology, and the Center for Molecular and Vascular Biology,University of Leuven, Leuven, Belgium

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 1, 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.

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