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

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 arte...

Full description

Saved in:
Bibliographic Details
Published in:Pflügers Archiv 2015-09, Vol.467 (9), p.1997-2009
Main Authors: Chaston, Daniel J., Haddock, Rebecca E., Howitt, Lauren, Morton, Susan K., Brown, Russell D., Matthaei, Klaus I., Hill, Caryl E.
Format: Article
Language:English
Subjects:
Animals
Biomedical and Life Sciences
Biomedicine
Blood Pressure
Cell Biology
Connexins - genetics
Connexins - metabolism
Endothelium, Vascular - physiopathology
Gap Junction alpha-5 Protein
Human Physiology
Hypertension - physiopathology
Male
Membrane Potentials
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molecular Medicine
Neurosciences
Organ Physiology
Patch-Clamp Techniques
Potassium Channels, Calcium-Activated - metabolism
Receptors
Vasodilation - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 (N ɷ -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 SK Ca and IK Ca channels, was significantly reduced in Cx40T202STg mice, due to attenuation of the SK Ca 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 SK Ca -dependent hyperpolarisation and also increases blood pressure.
ISSN:0031-6768
1432-2013
DOI:10.1007/s00424-014-1640-x