Abstract
Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1α and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs.
Footnotes
- Received December 23, 2013.
- Accepted March 27, 2014.
This research was supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants R01-NS063965 (to S.C.F.) and R21-NS063965 (to A.E.)]; the National Institutes of Health National Eye Institute [Grant R01-EY022408 (to A.B.E.)]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL103952 (to P.R.S.)]; the U.S. Department of Veterans Affairs Merit Review [Grants BX000891 (to S.C.F.) and BX000347 (to A.E.)]; and the American Heart Association [Grant 12PRE12030197 (to S.S.)]. The contents do not represent the views of the funding agencies, the Department of Veterans Affairs, or the U.S. government.
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- U.S. Government work not protected by U.S. copyright
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