Journal
STROKE
Volume 40, Issue 7, Pages 2532-2538Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.108.545095
Keywords
angiogenesis; eNOS; HDL-C; stroke; TO901317
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Funding
- National Institute on Aging [RO1 AG031811]
- National Institute of Neurological Diseases and Stroke [RO1 NS047682, PO1 NS23393]
- American Heart Association [0750048Z]
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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. (Stroke. 2009; 40: 2532-2538.)
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