Disruption of vascular Ca2+-activated chloride currents lowers blood pressure
Disruption of vascular Ca2+-activated chloride currents lowers blood pressure
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DOI：
10.1172/jci70025
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Huebner, Christian A.
中科院分区：
文献类型：
--
作者：
Heinze, Christoph;Seniuk, Anika;Huebner, Christian A.
高血压是全球死亡的主要危险因素。其特征之一是外周血管阻力的增加，这在很大程度上取决于小动脉张力。血管平滑肌细胞（VSMC）中的Ca 2+激活的氯电流（CaCCs）是增加血管收缩性的候选者。我们分析了血管树并在主动脉和颈动脉的VSMC中鉴定了大量的CaCC。培养基中VSMCs中CaCC较小或不存在。大血管，如肠系膜动脉和较大的视网膜小动脉。在视网膜、脑和骨骼肌的小血管中，收缩性中间细胞或周细胞逐渐取代VSMC，CaCC特别大。靶向破坏VSMC、中间细胞和周细胞中的钙激活氯离子通道TMEM 16 A（也称为ANO 1）消除了所有研究血管中的CaCC。缺乏血管TMEM 16 A的小鼠在血管收缩剂治疗后全身血压较低，高血压反应也减少。中型肠系膜动脉的收缩性没有差异;然而，主动脉和视网膜小动脉对血管收缩诱导药物U46619的反应性降低。TMEM 16 A也是外周血管收缩所需的，因为在来自突变小鼠的分离灌注后肢中对U46619的反应减弱。我们的数据表明，TMEM 16 A在小动脉和毛细血管血流中起着普遍的作用，是治疗高血压的一个有希望的靶点。
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.