title: Leptin potentiates endothelium-dependent relaxation by inducing endothelial expression of neuronal NO synthase.
abstract: OBJECTIVE
  Obesity is associated with hyperleptinemia but it is not clear whether leptin protects vascular function or promotes dysfunction. We therefore studied the consequences of hyperleptinemia in lean mice.
  
  
  RESULTS
  Wild-type and endothelial NO synthase (eNOS)(-/-) mice were infused with leptin (0.4 mg/kg per day, 7 days), and endothelium-dependent relaxation was studied in aortic segments. Leptin had no effect on acetylcholine-induced endothelium-dependent relaxation in normal wild-type mice but restored endothelium-dependent relaxation in wild-type mice treated with angiotensin II (0.7 mg/kg per day, 7 days) to induce endothelial dysfunction. Leptin also sensitized aortae from eNOS(-/-) mice to acetylcholine, an effect blocked by neuronal NOS (nNOS) inhibition and not observed in eNOS-nNOS double(-/-) mice. Consistent with these findings, leptin induced nNOS expression in murine and human vessels and human endothelial but not smooth muscle cells. Aortic nNOS expression was also induced in mice by a high-fat diet. Mechanistically, leptin increased endothelial Janus kinase 2 and signal transducer and activator of transcription 3 phosphorylation, and inhibition of Janus kinase 2 prevented nNOS induction in cultured cells and leptin-induced relaxations in eNOS(-/-) mice.
  
  
  CONCLUSIONS
  Leptin induces endothelial nNOS expression, which compensates, in part, for a lack of NO production by eNOS to maintain endothelium-dependent relaxation.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Benkhoff
authors.forename: Annemarieke E
authors.initials: AE
authors.lastname: Loot
authors.forename: Ina
authors.initials: I
authors.lastname: Pierson
authors.forename: Adrian
authors.initials: A
authors.lastname: Sturza
authors.forename: Karin
authors.initials: K
authors.lastname: Kohlstedt
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Olaf
authors.initials: O
authors.lastname: Grisk
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000201:enzymology; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D000109:Acetylcholine