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

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d4939135e307">Objective</h5> <p id="P1">Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator of arteriolar vasoconstriction, vascular resistance, and blood pressure (BP). Importantly, α-adrenergic receptor stimulation, which uniquely couples with Pannexin 1 (Panx1) channel-mediated ATP release channels in resistance arteries, also requires localization to membrane caveolae. Here we test if localization of Panx1 to caveolin-1 promotes channel function (stimulus-dependent ATP release and adrenergic vasoconstriction) and is important for BP homeostasis. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d4939135e312">Approach and Results</h5> <p id="P2">We use <i>in vitro</i> VSMC culture models, <i>ex vivo</i> resistance arteries, and a novel inducible VSMC-specific caveolin-1 knockout mouse to probe interactions between Panx1 and caveolin-1. We report that Panx1 and caveolin-1 co-localized on the VSMC plasma membrane of resistance arteries near sympathetic nerves in an adrenergic stimulus-dependent manner. Genetic deletion of caveolin-1 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 mmHg; Night= 7 mmHg) occurred in mice deficient for VSMC caveolin-1. These animals were resistant to further BP lowering using a Panx1 peptide inhibitor PxIL2P1, which targets an intracellular loop region necessary for channel function. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d4939135e323">Conclusions</h5> <p id="P3">Translocalization of Panx1 to caveolin-1-enriched caveolae in VSMCs augments the release of purinergic stimuli necessary for proper adrenergic-mediated vasoconstriction and BP homeostasis. </p> </div>

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Caveolae as plasma membrane sensors, protectors and organizers.

Robert Parton, Miguel del Pozo (2013)

Caveolae are submicroscopic, plasma membrane pits that are abundant in many mammalian cell types. The past few years have seen a quantum leap in our understanding of the formation, dynamics and functions of these enigmatic structures. Caveolae have now emerged as vital plasma membrane sensors that can respond to plasma membrane stresses and remodel the extracellular environment. Caveolae at the plasma membrane can be removed by endocytosis to regulate their surface density or can be disassembled and their structural components degraded. Coat proteins, called cavins, work together with caveolins to regulate the formation of caveolae but also have the potential to dynamically transmit signals that originate in caveolae to various cellular destinations. The importance of caveolae as protective elements in the plasma membrane, and as membrane organizers and sensors, is highlighted by links between caveolae dysfunction and human diseases, including muscular dystrophies and cancer.

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Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins.

Kyle Cowan, Donglin Bai, Douglas B. Cowan … (2007)

Pannexins are mammalian orthologs of the invertebrate gap junction proteins innexins and thus have been proposed to play a role in gap junctional intercellular communication. Localization of exogenously expressed pannexin 1 (Panx1) and pannexin 3 (Panx3), together with pharmacological studies, revealed a cell surface distribution profile and life cycle dynamics that were distinct from connexin 43 (Cx43, encoded by Gja1). Furthermore, N-glycosidase treatment showed that both Panx1 (approximately 41-48 kD species) and Panx3 (approximately 43 kD) were glycosylated, whereas N-linked glycosylation-defective mutants exhibited a decreased ability to be transported to the cell surface. Tissue surveys revealed the expression of Panx1 in several murine tissues--including in cartilage, skin, spleen and brain--whereas Panx3 expression was prevalent in skin and cartilage with a second higher-molecular-weight species present in a broad range of tissues. Tissue-specific localization patterns of Panx1 and Panx3 ranging from distinct cell surface clusters to intracellular profiles were revealed by immunostaining of skin and spleen sections. Finally, functional assays in cultured cells transiently expressing Panx1 and Panx3 were incapable of forming intercellular channels, but assembled into functional cell surface channels. Collectively, these studies show that Panx1 and Panx3 have many characteristics that are distinct from Cx43 and that these proteins probably play an important biological role as single membrane channels.

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Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities.

Jerome Combs, Michael Lisanti, Linda A. Jelicks … (2002)

Caveolae organelles and caveolin-1 protein expression are most abundant in adipocytes and endothelial cells. Our initial report on mice lacking caveolin-1 (Cav-1) demonstrated a loss of caveolae and perturbations in endothelial cell function. More recently, however, observation of the Cav-1-deficient cohorts into old age revealed significantly lower body weights, as compared with wild-type controls. These results suggest that Cav-1 null mice may have problems with lipid metabolism and/or adipocyte functioning. To test this hypothesis directly, we placed a cohort of wild-type and Cav-1 null mice on a high fat diet. Interestingly, despite being hyperphagic, Cav-1 null mice show overt resistance to diet-induced obesity. As predicted, adipocytes from Cav-1 null null mice lack caveolae membranes. Early on, a lack of caveolin-1 selectively affects only the female mammary gland fat pad and results in a near complete ablation of the hypo-dermal fat layer. There are also indications of generalized adipose tissue pathology. With increasing age, a systemic decompensation in lipid accumulation occurs resulting in dramatically smaller fat pads, histologically reduced adipocyte cell diameter, and a poorly differentiated/hypercellular white adipose parenchyma. To gain mechanistic insights into this phenotype, we show that, although serum insulin, glucose, and cholesterol levels are entirely normal, Cav-1 null mice have severely elevated triglyceride and free fatty acid levels, especially in the post-prandial state. However, this build-up of triglyceride-rich chylomicrons/very low density lipoproteins is not due to perturbed lipoprotein lipase activity, a major culprit of isolated hypertriglyceridemia. The lean body phenotype and metabolic defects observed in Cav-1 null mice are consistent with the previously proposed functions of caveolin-1 and caveolae in adipocytes. Our results show for the first time a clear role for caveolins in systemic lipid homeostasis in vivo and place caveolin-1/caveolae as major factors in hyperlipidemias and obesity.

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Author and article information

Journal

Title: Arteriosclerosis, Thrombosis, and Vascular Biology

Abbreviated Title: ATVB

Publisher: Ovid Technologies (Wolters Kluwer Health)

ISSN (Print): 1079-5642

ISSN (Electronic): 1524-4636

Publication date Created: September 2018

Publication date (Print): September 2018

Volume: 38

Issue: 9

Pages: 2065-2078

Affiliations

[1 ]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.)

[2 ]Department of Pharmacology (L.J.D., A.S.K.), University of Virginia School of Medicine, Charlottesville

[3 ]Department of Medicine (J.C.)

[4 ]Division of Medical Sciences, Centre for Biomedical Research, University of Victoria, British Columbia, Canada (A.K.J.B., L.A.S.)

[5 ]Department of Molecular Physiology and Biophysics, University of Virginia, Charlottesville (M.V.A., T.C.S.K., A.V.S., B.E.I.)

[6 ]Department of Biomedical Engineering, University of Virginia School of Engineering, Charlottesville (E.L.M.)

[7 ]Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada (S.P.)

[8 ]Molecular and Clinical Sciences Research Institute, St. George’s University London, United Kingdom (I.A.G.)

[9 ]Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis (R.F.M.).

[10 ]Department of Pharmacology and Department of Anesthesiology (R.D.M.), The University of Illinois at Chicago

Article

DOI: 10.1161/ATVBAHA.118.311290

PMC ID: 6202122

PubMed ID: 30026274

SO-VID: 0efdb257-8bff-4eea-8f4d-5952ee6276c2

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

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Probing cerebral hemodynamics with BOLD fMRI

Most cited references 62

Caveolae as plasma membrane sensors, protectors and organizers.

Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins.

Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities.

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