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Disruption of vascular Ca2+-activated chloride currents lowers blood pressure
Christoph Heinze, … , Björn C. Schroeder, Christian A. Hübner
Christoph Heinze, … , Björn C. Schroeder, Christian A. Hübner
Published January 9, 2014
Citation Information: J Clin Invest. 2014;124(2):675-686. https://doi.org/10.1172/JCI70025.
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Research Article Vascular biology Article has an altmetric score of 21

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

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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.

Authors

Christoph Heinze, Anika Seniuk, Maxim V. Sokolov, Antje K. Huebner, Agnieszka E. Klementowicz, István A. Szijártó, Johanna Schleifenbaum, Helga Vitzthum, Maik Gollasch, Heimo Ehmke, Björn C. Schroeder, Christian A. Hübner

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Figure 4

TMEM16A is expressed in small arterioles of brain and retina and enhances contractility in the retina.

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TMEM16A is expressed in small arterioles of brain and retina and enhance...
(A) Immunostaining of brain slices for the endothelial cell marker CD31 (upper) and TMEM16A (middle); the bottom panel shows an overlay. Small but not large arterioles show strong TMEM16A staining. Scale bar: 50 εm. (B) Epifluorescence images of retinal whole mount preparation stained for smooth muscle actin (SMA, upper) and TMEM16A (lower). Primary arterioles (a) and primary veins (v) originate from the optical disc in an alternate manner. Whereas TMEM16A staining in primary arterioles was absent or week, secondary and higher-order arterioles were intensely labeled. Scale bar: 300 εm. (C) Retina whole mount immunostainings for CD31 (upper) and TMEM16A (middle) showing a TMEM16A-negative primary arteriole (arrowhead) and second- and higher order arteriolar branches and overlay (lower). Arrows indicate strongly labeled cells at branching points of second-order arterioles. Scale bar: 30 εm. (D) Typical wild-type currents recorded from retina tissue prints of VSMC-like cells of first-order arterioles and (E) dome-shaped cells primarily found on second/third-order arterioles. The voltage protocol for D and E is shown in D. (F) CaCCs were absent in contractile cells of conditional knockout mice. (G) Mean tail current densities of contractile cells of the retina and brain arterioles for different genotypes and comparison with currents from VSMCs of the aorta (n = 6–17 each). (H) Constriction of second/third-order arterioles was diminished in the absence of CaCCs. Dose-response curves for U46619 in non-induced control and conditional Tmem16a knockout mice (n = 60 each). Student’s t test; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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