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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 5

TMEM16A modulates peripheral resistance.

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TMEM16A modulates peripheral resistance.
(A) Double immunostaining for C...
(A) Double immunostaining for CD31 (left) and TMEM16A (center) of slices from skeletal muscle. The overlay is shown on the right. Scale bar: 50 εm. (B and C) I-V relationship (B) and tail current density (C) from isolated pericytes from skeletal muscle showed a drastic reduction of CaCCs upon disruption of TMEM16A (n = 13–16 cells each). **P < 0.01. (D) Resting membrane potentials of isolated skeletal muscle pericytes did not differ between genotypes. n = 6; Student’s t test; P > 0.05. (E) U46619-induced depolarization of WT pericytes was almost absent in the mutant. TMEM16A-deficient pericytes hyperpolarized after agonist application, which suggests the presence of Ca2+-activated K+ channels. Replacing Cl– with methanesulfonate further increased the depolarization in WT, but not in mutant pericytes, indicating that Cl– ion flow is important for U46619-induced pericyte depolarization. n = 6; Student’s t test; **P < 0.01. (F) Original tracing of the perfusion pressure of an isolated hind limb perfusion of a control mouse. The bolus injection of either 20 pmol or 60 pmol U46619 (arrows) caused a short pressure peak because of the injected volume and subsequently a protracted pressure increase. The peak responses are indicated by arrowheads. (G) The difference between peak and steady-state pressure at the two doses of U46619 analyzed. perf., perfusion. n = 20. Student’s t test; *P < 0.05.

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