title: eNOS mediates TO90317 treatment-induced angiogenesis and functional outcome after stroke in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. jieli@neuro.hfh.edu
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood; D004268:DNA-Binding Proteins / Q000819:agonists*; D004195:Disease Models, Animal; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology* / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D052250:Nitric Oxide Synthase Type III; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides