Vascular Endothelial Growth Factor Promotes Pericyte Coverage of Brain Capillaries, Improves Cerebral Blood Flow During Subsequent Focal Cerebral Ischemia, and Preserves the Metabolic Penumbra

Abstract

Background and Purpose— Therapeutic angiogenesis aims at improving cerebral blood flow by amplification of vascular sprouting, thus promoting tissue survival under conditions of subsequent ischemia. It remains unknown whether induced angiogenesis leads to the formation of functional vessels that indeed result in hemodynamic improvements. Observations of hemodynamic steal phenomena and disturbed neurovascular integrity after vascular endothelial growth factor delivery questioned the concept of therapeutic angiogenesis. Methods— Mice were treated with recombinant human vascular endothelial growth factor (0.02 μg/d; intracerebroventricular) for 3 to 21 days and subsequently exposed to 90-minute middle cerebral artery occlusion. Angiogenesis, histological brain injury, IgG extravasation, cerebral blood flow, protein synthesis and energy state, and pericyte coverage on brain capillaries were evaluated in a multiparametric approach combining histochemical, autoradiographic, and regional bioluminescence techniques. Results— Vascular endothelial growth factor increased brain capillary density within 10 days and reduced infarct volume and inflammation after subsequent middle cerebral artery occlusion, and, when delivered for prolonged periods of 21 days, enhanced postischemic blood–brain barrier integrity. Increased cerebral blood flow was noted in ischemic brain areas exhibiting enhanced angiogenesis and was associated with preservation of the metabolic penumbra, defined as brain tissue in which protein synthesis has been suppressed but ATP preserved. Vascular endothelial growth factor enhanced pericyte coverage of brain endothelial cells via mechanisms involving increased N-cadherin expression on cerebral microvessels. Conclusions— That cerebral blood flow is increased during subsequent ischemic episodes, leading to the stabilization of cerebral energy state, fosters hope that by promoting new vessel formation brain tissue survival may be improved.