Hypercholesterolemia worsens the blood flow deficit in focal cerebral ischemia in the absence of atherosclerosis

Background and aims: Hypercholesterolemia may increase stroke risk by accelerating atherosclerosis and narrowing luminal diameter in cerebral vessels as well as disrupting vascular endothelial and smooth muscle function. We tested the hypothesis that that hypercholesterolemia impairs cerebrovascular function and worsens cerebral blood flow (CBF) deficit and tissue outcome after focal ischemia even in the absence of hemodynamically significant vessel narrowing. Methods: We tested this hypothesis in ApoE knockout (KO) mice using high spatiotemporal resolution laser speckle flowmetry through intact skull noninvasively, and studied the hemodynamic impact of hypercholesterolemia on the evolution of CBF deficit in focal cerebral ischemia. Wild type (WT, C57BL/6), ApoE KO or ApoE/eNOS double KO mice were fed high-fat quot;westernquot; diet for 4, 8, or 10 weeks starting at 4 weeks of age. Histopathological examination of extracranial arteries in 14 week-old ApoE KO showed only minimal atherosclerotic changes such as fatty streaks with subendothelial foam cells. Intracranial arteries did not develop atherosclerotic lesions even after 12 months, despite severe extracranial atherosclerosis. Results: Mean arterial blood pressure was higher in ApoE KO compared to WT in all age groups (94+/-2 vs. 85+/-2 mmHg, respectively; n=17 each, p