Candesartan Augments Ischemia-Induced Proangiogenic State and Results in Sustained Improvement After Stroke

Abstract

Background and Purpose— We have shown that acute treatment with candesartan in an experimental model of stroke resulted in vascular protection and improved outcomes at 24 hours poststroke, but the mechanisms are unknown. We now examine effects of candesartan on proangiogenic factors and 7-day outcomes using the same treatment paradigm. Methods— Male Wistar rats underwent 3 hours of middle cerebral artery occlusion followed by reperfusion. A single dose of 1 mg/kg candesartan intravenously was given at reperfusion. Animals received neurobehavioral testing before middle cerebral artery occlusion, at 24 hours after middle cerebral artery occlusion, and at 7 days. Blood pressure was measured by telemetry. Animals euthanized at 24 hours had brain tissue and cerebrospinal fluid collected for matrix metalloproteinase activity, vascular endothelial growth factor expression, and tube formation assay. Neurobehavioral testing included elevated body swing test, Bederson, beam walk, and paw grasp. Cerebrovascular density was quantified using immunohistochemistry at 24 hours and 7 days. Results— Matrix metalloproteinase-2 activity and vascular endothelial growth factor expression were higher ( P =0.035, P =0.042, respectively) and cerebrospinal fluid was significantly more proangiogenic (5× tube formation; P =0.002) in the candesartan group at 24 hours. Although no difference was seen in infarct size at 7 days, treatment improved Bederson scores (2.1 versus 2.9, P =0.0083), elevated body swing test (22.9 versus 39.4, P =0.021), and paw grasp (1.29 versus 2.88, P =0.0001) at 7 days. Candesartan treatment resulted in increased vascular density in the striatum at 7 days ( P =0.037). Conclusion— Candesartan after reperfusion augments ischemia-induced angiogenic state and provides long-term benefits. The beneficial effects may involve vascular protection and enhancement of early angiogenic remodeling.