Survivin-dependent angiogenesis in ischemic brain: molecular mechanisms of hypoxia-induced up-regulation.

Abstract

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.

• Authors: Edward M Conway, Femke Zwerts, Veerle Van Eygen, Astrid DeVriese, Nobuo Nagai, Wei Luo, Désiré Collen
• Journal: The American journal of pathology (Am J Pathol) Vol. 163 Issue 3 Pg. 935-46 (Sep 2003) ISSN: 0002-9440 [Print] United States
• PMID: 12937134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• Endothelial Growth Factors
• Inhibitor of Apoptosis Proteins
• Intercellular Signaling Peptides and Proteins
• Lymphokines
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Survivin
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Oxygen

Topics

• Animals
• Arterial Occlusive Diseases (complications, metabolism, physiopathology)
• Blood Vessels (physiopathology)
• Brain (physiopathology)
• Brain Ischemia (complications, etiology, physiopathology)
• Cells, Cultured
• Cerebral Arteries
• Endothelial Growth Factors (metabolism)
• Hypoxia, Brain (etiology, metabolism)
• Inhibitor of Apoptosis Proteins
• Intercellular Signaling Peptides and Proteins (metabolism)
• Lymphokines (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Microtubule-Associated Proteins (metabolism)
• Neoplasm Proteins
• Neovascularization, Physiologic
• Oxygen (metabolism)
• Survivin
• Up-Regulation
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors