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(Stroke. 2009;40:2532.)
© 2009 American Heart Association, Inc.

Original Contributions

eNOS Mediates TO90317 Treatment-Induced Angiogenesis and Functional Outcome After Stroke in Mice

Jieli Chen, MD; Xu Cui, PhD; Alex Zacharek, MS; Cynthia Roberts, BS Michael Chopp, PhD

From the Department of Neurology (J.C., X.C., A.Z., C.R., M.C.), Henry Ford Hospital, Detroit, Mich; and the Department of Physics (M.C.), Oakland University, Rochester, Mich.

Correspondence to Jieli Chen, MD, Neurology Research, E&R Building, Room 3091, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202. E-mail jieli{at}neuro.hfh.edu

Background and Purpose— TO901317, a synthetic liver X receptor agonist, elevates high-density lipoprotein cholesterol (HDL-C) in mice. We tested the hypothesis that TO901317 treatment of stroke promotes angiogenesis and vascular maturation and improves functional outcome after stroke by increasing endothelial nitric oxide synthase (eNOS) phosphorylation.

Methods— C57BL/6J mice were subjected to middle cerebral artery occlusion and were treated with or without TO901317 (30 mg/kg) starting 24 hours after middle cerebral artery occlusion and daily for 14 days.

Results— TO901317 significantly increased serum HDL-C level, promoted angiogenesis and vascular stabilization in the ischemic brain, and improved functional outcome after stroke. The increased HDL-C level significantly correlated with functional recovery after stroke. TO901317 also increased eNOS phosphorylation in the ischemic brain. Mechanisms underlying the TO901317-induced angiogenesis were investigated using eNOS knockout (eNOS–/–) mice. TO901317 treatment of eNOS–/– mice significantly increased HDL-C level but failed to increase angiogenesis and functional outcome after stroke. In vitro studies demonstrated that TO901317 and HDL-C significantly increased capillary tube formation and promoted eNOS phosphorylation activity in cultured mouse brain endothelial cells compared with nontreatment controls. However, TO901317 and high-density lipoprotein treatment-induced capillary tube formation were absent in eNOS-deficient mouse brain endothelial cell.

Conclusions— These data indicate that TO901317 treatment increases serum HDL-C level, which promotes angiogenesis through eNOS and leads to improvement of functional outcome after stroke.

Key Words: angiogenesis • eNOS • HDL-C • stroke • TO901317