Anatomy and Cell Biology Publications

Title

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

Authors

Leon J. DeLalio, Robert M. Berne Cardiovascular Research Center & Department of Pharmacology University of Virginia School of Medicine, Charlottesville
Alexander S. Keller, Robert M. Berne Cardiovascular Research Center & Department of Pharmacology University of Virginia School of Medicine, Charlottesville
Jiwang Chen, Department of Medicine
Andrew K.J. Boyce, Division of Medical Sciences, Centre for Biomedical Research, University of Victoria
Mykhaylo V. Artamonov, Department of Molecular Physiology and Biophysics, University of Virginia
Henry R. Askew-Page, Robert M. Berne Cardiovascular Research Center
T.C.Stevenson Keller, Robert M. Berne Cardiovascular Research Center & Department of Molecular Physiology and Biophysics, University of Virginia
Scott R. Johnstone, Robert M. Berne Cardiovascular Research Center
Rachel B. Weaver, Robert M. Berne Cardiovascular Research Center
Miranda E. Good, Robert M. Berne Cardiovascular Research Center
Sara A. Murphy, Robert M. Berne Cardiovascular Research Center
Angela K. Best, Robert M. Berne Cardiovascular Research Center
Ellen L. Mintz, Department of Biomedical Engineering, University of Virginia School of Engineering
Silvia Penuela, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario
Iain A. Greenwood, Molecular and Clinical Sciences Research Institute, St. George's University London
Roberto F. Machado, Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine
Avril V. Somlyo, Department of Molecular Physiology and Biophysics, University of Virginia
Leigh Anne Swayne, Division of Medical Sciences, Centre for Biomedical Research, University of Victoria
Richard D. Minshall, Department of Pharmacology and Department of Anesthesiology, The University of Illinois at Chicago
Brant E. Isakson, Robert M. Berne Cardiovascular Research Center & Department of Molecular Physiology and Biophysics, University of Virginia

Document Type

Article

Publication Date

9-2018

Issue

9

Journal

Arteriosclerosis Thrombosis and Vascular Biology

Volume

38

First Page

2065

Last Page

2078

URL with Digital Object Identifier

https://doi.org/10.1161/ATVBAHA.118.311290

Abstract

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.

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