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Perturbation of chemical coupling by an endothelial Cx40 mutant attenuates endothelium-dependent vasodilation by KCa channels and elevates blood pressure in mice

  • Organ physiology
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Abstract

Mutant forms of connexin40 (Cx40) exist in the human population and predispose carriers to atrial fibrillation. Since endothelial expression of Cx40 is important for electrical and chemical communication within the arterial wall, carriers of mutant Cx40 proteins may be predisposed to peripheral arterial dysfunction and dysregulation of blood pressure. We have therefore studied mice expressing either a chemically dysfunctional mutant, Cx40T202S, or wild-type Cx40, with native Cx40, specifically in the endothelium. Blood pressure was measured by telemetry under normal conditions and during cardiovascular stress induced by locomotor activity, phenylephrine or nitric oxide blockade (Nɷ-nitro-l-arginine methyl ester hydroxide, L-NAME). Blood pressure of Cx40T202STg mice was significantly elevated at night when compared with wild-type or Cx40Tg mice, without change in mean heart rate, pulse pressure or locomotor activity. Analysis over 24 h showed that blood pressure of Cx40T202STg mice was significantly elevated at rest and additionally during locomotor activity. In contrast, neither plasma renin concentration nor pressor responses to phenylephrine or L-NAME were altered, the latter indicating that nitric oxide bioavailability was normal. In isolated, pressurised mesenteric arteries, hyperpolarisation and vasodilation evoked by SKA-31, the selective modulator of SKCa and IKCa channels, was significantly reduced in Cx40T202STg mice, due to attenuation of the SKCa component. Acetylcholine-induced ascending vasodilation in vivo was also significantly attenuated in cremaster muscle arterioles of Cx40T202STg mice, compared to wild-type and Cx40Tg mice. We conclude that endothelial expression of the chemically dysfunctional Cx40T202S reduces peripheral vasodilator capacity mediated by SKCa-dependent hyperpolarisation and also increases blood pressure.

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Acknowledgments

This work was supported by the National Health and Medical Research Council of Australia [grant number 471421] and Heart Foundation of Australia [grant number G12C 6361].

Conflict of Interest

None declared.

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Authors and Affiliations

  1. John Curtin School of Medical Research, Australian National University, Canberra, ACT, 0200, Australia

    Daniel J. Chaston, Rebecca E. Haddock, Lauren Howitt, Susan K. Morton, Klaus I. Matthaei & Caryl E. Hill

  2. Department of Physiology, Monash University, Melbourne, Victoria, 3800, Australia

    Russell D. Brown

  3. Eccles Institute of Neuroscience, The Australian National University, Building 131, Garran Road, Acton, ACT, 2601, Australia

    Caryl E. Hill

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  1. Daniel J. Chaston
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Correspondence to Caryl E. Hill.

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Rebecca E. Haddock and Lauren Howitt contributed equally.

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Chaston, D.J., Haddock, R.E., Howitt, L. et al. Perturbation of chemical coupling by an endothelial Cx40 mutant attenuates endothelium-dependent vasodilation by KCa channels and elevates blood pressure in mice. Pflugers Arch - Eur J Physiol 467, 1997–2009 (2015). https://doi.org/10.1007/s00424-014-1640-x

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  • DOI: https://doi.org/10.1007/s00424-014-1640-x

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