t0901317 and Infarction--Middle-Cerebral-Artery

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.. 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.. 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.. 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.

Topics: Animals; Cholesterol, HDL; Disease Models, Animal; DNA-Binding Proteins; Hydrocarbons, Fluorinated; Infarction, Middle Cerebral Artery; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Stroke; Sulfonamides; Treatment Outcome