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Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

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Item Type:Article
Title:Disruption of vascular Ca2+-activated chloride currents lowers blood pressure
Creators Name:Heinze, C., Seniuk, A., Sokolov, M.V., Huebner, A.K., Klementowicz, A.E., Szijártó, I.A., Schleifenbaum, J., Vitzthum, H., Gollasch, M., Ehmke, H., Schroeder, B.C. and Hübner, C.A.
Abstract:High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca2+-activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstriction-inducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension.
Keywords:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Arterioles, Blood Pressure, Brain, Chloride Channels, Molecular Cloning, Complementary DNA, Electrophysiology, Estrogen Antagonists, HEK293 Cells, Hypertension, Membrane Potentials, Mesenteric Arteries, Vascular Smooth Muscle, Neoplasm Proteins, Pericytes, Retina, Tamoxifen, Time Factors, Vascular Resistance, Vasoconstrictor Agents, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:675-686
Date:3 February 2014
Official Publication:https://doi.org/10.1172/JCI70025
PubMed:View item in PubMed

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