title: α-Melanocyte-stimulating hormone regulates vascular NO availability and protects against endothelial dysfunction.
abstract: OBJECTIVE
  α-Melanocyte-stimulating hormone (α-MSH), derived from the precursor molecule pro-opiomelanocortin, exerts potent anti-inflammatory actions in the vasculature, but its role in circulatory regulation remains unclear. Therefore, we sought to investigate whether α-MSH could regulate the local control of blood vessel tone.
  
  
  RESULTS
  Using in vivo and ex vivo methods to assess vascular reactivity, we found that α-MSH improved endothelium-dependent vasodilatation in the mouse aorta and coronary circulation without directly contracting or relaxing blood vessels. α-MSH promoted vasodilatation by enhancing endothelial nitric oxide (NO) formation and by improving sensitivity to endothelium-independent blood vessel relaxation. Using cultured human endothelial cells to elucidate the involved molecular mechanisms, we show that α-MSH increased the expression and phosphorylation of endothelial NO synthase in these cells. The observed effects were regulated by melanocortin 1 (MC1) receptors expressed in the endothelium. In keeping with the vascular protective role of α-MSH, in vivo treatment with stable analogues of α-MSH ameliorated endothelial dysfunction associated with aging and diet-induced obesity in mice.
  
  
  CONCLUSIONS
  The present study identifies α-MSH and endothelial MC1 receptors as a new signalling pathway contributing to the regulation of NO availability and vascular function. These findings suggest applicability of α-MSH analogues for therapeutic use in pathological conditions that are characterized by vascular dysfunction.
authors.affiliation: Department of Pharmacology, Drug Development and Pharmaceutics, and Turku Center for Disease Modeling, Itäinen Pitkäkatu 4b, 20014 University of Turku, Turku, Finland. pperin@utu.fi
authors.forename: Petteri
authors.initials: P
authors.lastname: Rinne
authors.forename: Wendy
authors.initials: W
authors.lastname: Nordlund
authors.forename: Ilkka
authors.initials: I
authors.lastname: Heinonen
authors.forename: Anna-Maija
authors.initials: AM
authors.lastname: Penttinen
authors.forename: Antti
authors.initials: A
authors.lastname: Saraste
authors.forename: Suvi T
authors.initials: ST
authors.lastname: Ruohonen
authors.forename: Satu
authors.initials: S
authors.lastname: Mäkelä
authors.forename: Laura
authors.initials: L
authors.lastname: Vähätalo
authors.forename: Katja
authors.initials: K
authors.lastname: Kaipio
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: Saku
authors.initials: S
authors.lastname: Ruohonen
authors.forename: Eriika
authors.initials: E
authors.lastname: Savontaus
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D044102:Receptor, Melanocortin, Type 1 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects; D000521:alpha-MSH / Q000494:pharmacology*
chemical_list: D044102:Receptor, Melanocortin, Type 1; D009569:Nitric Oxide; D000521:alpha-MSH; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine