Polymorphism in endothelial connexin40 enhances sensitivity to intraluminal pressure and increases arterial stiffness

Daniel J. Chaston, Brett K. Baillie, T. Hilton Grayson, Raphael J. Courjaret, Jillian M. Heisler, Katherine A. Lau, Khaled MacHaca, Bruce J. Nicholson, Anthony Ashton, Klaus I. Matthaei, Caryl E. Hill

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19 Citations (Scopus)

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. APPROACH AND 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.

Original languageEnglish
Pages (from-to)962-970
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number5
DOIs
Publication statusPublished - 1 May 2013

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Keywords

  • arterial dysfunction
  • connexin40
  • endothelium
  • myogenic response
  • stiffness

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Chaston, D. J., Baillie, B. K., Grayson, T. H., Courjaret, R. J., Heisler, J. M., Lau, K. A., MacHaca, K., Nicholson, B. J., Ashton, A., Matthaei, K. I., & Hill, C. E. (2013). Polymorphism in endothelial connexin40 enhances sensitivity to intraluminal pressure and increases arterial stiffness. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(5), 962-970. https://doi.org/10.1161/ATVBAHA.112.300957