Disruption of vascular Ca2+-activated chloride currents lowers blood pressure
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Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. / Heinze, Christoph; Seniuk, Anika; Sokolov, Maxim V; Huebner, Antje K; Klementowicz, Agnieszka E; Szijártó, István A; Schleifenbaum, Johanna; Vitzthum, Helga; Gollasch, Maik; Ehmke, Heimo; Schroeder, Björn C; Hübner, Christian A.
in: J CLIN INVEST, Jahrgang 124, Nr. 2, 03.02.2014, S. 675-86.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Disruption of vascular Ca2+-activated chloride currents lowers blood pressure
AU - Heinze, Christoph
AU - Seniuk, Anika
AU - Sokolov, Maxim V
AU - Huebner, Antje K
AU - Klementowicz, Agnieszka E
AU - Szijártó, István A
AU - Schleifenbaum, Johanna
AU - Vitzthum, Helga
AU - Gollasch, Maik
AU - Ehmke, Heimo
AU - Schroeder, Björn C
AU - Hübner, Christian A
PY - 2014/2/3
Y1 - 2014/2/3
N2 - 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.
AB - 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.
KW - 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
KW - Animals
KW - Arterioles
KW - Blood Pressure
KW - Brain
KW - Chloride Channels
KW - Cloning, Molecular
KW - DNA, Complementary
KW - Electrophysiology
KW - Estrogen Antagonists
KW - HEK293 Cells
KW - Humans
KW - Hypertension
KW - Membrane Potentials
KW - Mesenteric Arteries
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Muscle, Smooth, Vascular
KW - Neoplasm Proteins
KW - Pericytes
KW - Retina
KW - Tamoxifen
KW - Time Factors
KW - Vascular Resistance
KW - Vasoconstrictor Agents
U2 - 10.1172/JCI70025
DO - 10.1172/JCI70025
M3 - SCORING: Journal article
C2 - 24401273
VL - 124
SP - 675
EP - 686
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 2
ER -