Hyperlipidemia Attenuates Vascular Endothelial Growth Factor–Induced Angiogenesis, Impairs Cerebral Blood Flow, and Disturbs Stroke Recovery via Decreased Pericyte Coverage of Brain Endothelial Cells

Abstract

Objective— Therapeutic angiogenesis aims at the promotion of vascular growth, usually under conditions of atherosclerosis. It was unknown how hyperlipidemia, a risk factor that is closely associated with atherosclerosis of brain vessels in humans, influences vascular endothelial growth factor–induced angiogenesis and stroke recovery. Approach and Results— Wild-type and apolipoprotein-E (ApoE) −/− mice were kept on regular or cholesterol-rich diet for mimicking different severities of hyperlipidemia. Mice were treated intracerebroventricularly with recombinant human vascular endothelial growth factor for 21 days (0.02 µg/d) and subsequently subjected to 90-minute middle cerebral artery occlusion followed by 1 or 24 hours of reperfusion. Histochemical, autoradiographic, and regional bioluminescence techniques were used to evaluate effects of blood lipids on postischemic angiogenesis, histopathologic brain injury, cerebral blood flow, protein synthesis and energy state, and pericyte coverage of brain endothelial cells. Hyperlipidemia dose-dependently attenuated vascular endothelial growth factor–induced capillary formation and pericyte coverage of brain endothelial cells, abolishing the improvement of cerebral blood flow during subsequent stroke, resulting in the loss of the metabolic penumbra and increased brain infarction. The enhanced angiogenesis after vascular endothelial growth factor treatment was accompanied by increased expression of the adhesion protein N-cadherin, which mediates endothelial-pericytic interactions, in ischemic brain microvessels of wild-type mice on regular diet that was blunted in wild-type mice on Western diet and ApoE −/− mice on either diet. Conclusions— The compromised vessel formation and hemodynamics question the concept of therapeutic angiogenesis in ischemic stroke where hyperlipidemia is highly prevalent.