title: Polymorphism in endothelial connexin40 enhances sensitivity to intraluminal pressure and increases arterial stiffness.
abstract: OBJECTIVE
  To determine whether impairment of endothelial connexin40 (Cx40), an effect that can occur in hypertension and aging, contributes to the arterial dysfunction and stiffening in these conditions.
  
  
  RESULTS
  A new transgenic mouse strain, expressing a mutant Cx40, (Cx40T202S), specifically in the vascular endothelium, has been developed and characterized. This mutation produces nonfunctional hemichannels, whereas gap junctions containing the mutant are electrically, but not chemically, patent. Mesenteric resistance arteries from Cx40T202S mice showed increased sensitivity of the myogenic response to intraluminal pressure in vitro, compared with wild-type mice, whereas transgenic mice overexpressing native Cx40 (Cx40Tg) showed reduced sensitivity. In control and Cx40Tg mice, the sensitivity to pressure of myogenic constriction was modulated by both NO and endothelium-derived hyperpolarization; however, the endothelium-derived hyperpolarization component was absent in Cx40T202S arteries. Analysis of passive mechanical properties revealed that arterial stiffness was enhanced in vessels from Cx40T202S mice, but not in wild-type or Cx40Tg mice.
  
  
  CONCLUSIONS
  Introduction of a mutant form of Cx40 in the endogenous endothelial Cx40 population prevents endothelium-derived hyperpolarization activation during myogenic constriction, enhancing sensitivity to intraluminal pressure and increasing arterial stiffness. We conclude that genetic polymorphisms in endothelial Cx40 can contribute to the pathogenesis of arterial disease.
authors.affiliation: John Curtin School of Medical Research, The Australian National University, Bldg 131 Garran Rd, Acton Australian Capital Territory 0200 Australia. daniel.chaston@anu.edu.au
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Chaston
authors.forename: Brett K
authors.initials: BK
authors.lastname: Baillie
authors.forename: T Hilton
authors.initials: TH
authors.lastname: Grayson
authors.forename: Raphael J
authors.initials: RJ
authors.lastname: Courjaret
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Heisler
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Lau
authors.forename: Khaled
authors.initials: K
authors.lastname: Machaca
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Nicholson
authors.forename: Anthony
authors.initials: A
authors.lastname: Ashton
authors.forename: Klaus I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: Caryl E
authors.initials: CE
authors.lastname: Hill
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D017630:Connexins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004553:Electric Conductivity; D004730:Endothelium, Vascular / Q000378:metabolism*; D017629:Gap Junctions / Q000502:physiology; D006339:Heart Rate; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D059289:Vascular Stiffness; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein
chemical_list: D017630:Connexins; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein