title: Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation.
abstract: OBJECTIVE
  Pre-menopausal females have a lower incidence of cardiovascular disease compared with age-matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium-derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex hormones, we investigated whether NO-mediated moderation of myogenic tone differed between the sexes.
  
  
  METHODS
  Pressure-diameter or relaxation concentration-response curves to the NO donor spermine-NO or soluble guanylate cyclase (sGC) stimulation (BAY41-2272) were constructed before and following drug intervention in murine mesenteric resistance arteries. Hypotensive responses to activators of the NO-sGC pathway were determined. Quantitative PCR and Western blotting were used for expression analysis.
  
  
  RESULTS
  NO synthase inhibition enhanced myogenic tone of arteries of both sexes while block of endothelium-derived hyperpolarizing factor (EDHF) enhanced responses in arteries of females only. Spermine-NO concentration-dependently relaxed mesenteric arteries isolated from either sex. However, while inhibition of sGC activity attenuated responses of arteries from male mice only, endothelial denudation attenuated responses of arteries from females only. BAY41-2272 and spermine-NO-induced vasodilatation and hypotension were greater in males than in females.
  
  
  CONCLUSIONS
  NO moderated myogenic tone in arteries of male mice by a sGC-dependent pathway while EDHF was the predominant endothelial regulator in arteries of females. This is a potentially important sexual dimorphism in NO-mediated reactivity and further implicates EDHF as the predominant endothelial vasodilator in female resistance arteries.
authors.affiliation: William Harvey Research Institute, Barts and The London Medical School, London, UK.
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Chan
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Bubb
authors.forename: Alastair
authors.initials: A
authors.lastname: Noyce
authors.forename: Inmaculada C
authors.initials: IC
authors.lastname: Villar
authors.forename: Johan
authors.initials: J
authors.lastname: Duchene
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
authors.forename: Ramona S
authors.initials: RS
authors.lastname: Scotland
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D011464:Epoprostenol / Q000502:physiology; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D006706:Homeostasis; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011312:Pressure; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012727:Sex Characteristics; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D001685:Biological Factors; D020030:Nitric Oxide Donors; D011720:Pyrazoles; D011725:Pyridines; C067410:endothelium-dependent hyperpolarization factor; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D011464:Epoprostenol; D006162:Guanylate Cyclase