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Arterioscler Thromb Vasc Biol. 2018 Sep;38(9):2065-2078. doi: 10.1161/ATVBAHA.118.311290.

Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure.

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From the Robert M. Berne Cardiovascular Research Center (L.J.D., A.S.K., H.R.A.-P., T.C.S.K., S.R.J., R.B.W., M.E.G., S.A.M., A.K.B., B.E.I.).
Department of Pharmacology (L.J.D., A.S.K.), University of Virginia School of Medicine, Charlottesville.
Department of Medicine (J.C.).
Division of Medical Sciences, Centre for Biomedical Research, University of Victoria, British Columbia, Canada (A.K.J.B., L.A.S.).
Department of Molecular Physiology and Biophysics, University of Virginia, Charlottesville (M.V.A., T.C.S.K., A.V.S., B.E.I.).
Department of Biomedical Engineering, University of Virginia School of Engineering, Charlottesville (E.L.M.).
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada (S.P.).
Molecular and Clinical Sciences Research Institute, St. George's University London, United Kingdom (I.A.G.).
Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis (R.F.M.).
Department of Pharmacology and Department of Anesthesiology (R.D.M.), The University of Illinois at Chicago.


Objective- Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator of arteriolar vasoconstriction, vascular resistance, and blood pressure. Importantly, α-adrenergic receptor stimulation, which uniquely couples with Panx1 (pannexin 1) channel-mediated ATP release in resistance arteries, also requires localization to membrane caveolae. Here, we test whether localization of Panx1 to Cav1 (caveolin-1) promotes channel function (stimulus-dependent ATP release and adrenergic vasoconstriction) and is important for blood pressure homeostasis. Approach and Results- We use in vitro VSMC culture models, ex vivo resistance arteries, and a novel inducible VSMC-specific Cav1 knockout mouse to probe interactions between Panx1 and Cav1. We report that Panx1 and Cav1 colocalized on the VSMC plasma membrane of resistance arteries near sympathetic nerves in an adrenergic stimulus-dependent manner. Genetic deletion of Cav1 significantly blunts adrenergic-stimulated ATP release and vasoconstriction, with no direct influence on endothelium-dependent vasodilation or cardiac function. A significant reduction in mean arterial pressure (total=4 mm Hg; night=7 mm Hg) occurred in mice deficient for VSMC Cav1. These animals were resistant to further blood pressure lowering using a Panx1 peptide inhibitor Px1IL2P, which targets an intracellular loop region necessary for channel function. Conclusions- Translocalization of Panx1 to Cav1-enriched caveolae in VSMCs augments the release of purinergic stimuli necessary for proper adrenergic-mediated vasoconstriction and blood pressure homeostasis.


Pannexin 1; adrenergic agents; blood pressure; caveolae; muscle, smooth

[Available on 2019-09-01]
[Indexed for MEDLINE]

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