NHE1 knockout reduces blood pressure and arterial media/lumen ratio with no effect on resting pHi in the vascular wall
NHE1 knockout reduces blood pressure and arterial media/lumen ratio with no effect on resting pHi in the vascular wall
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DOI：
10.1113/jphysiol.2011.227132
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发表时间：
2012-04-01
影响因子：
5.5
通讯作者：
Aalkjaer, Christian
中科院分区：
文献类型：
--
作者：
Boedtkjer, Ebbe;Damkier, Helle H.;Aalkjaer, Christian
血管壁中的酸碱转运仍不完全清楚。在这里，我们研究了（a）Na+/H+交换器NHE1敲除对血管平滑肌（VSMC）和内皮细胞（EC）pHi调节、肠系膜动脉形态、血管舒缩功能和血压调节的影响，以及（b）持续EC和VSMC酸化对血管舒缩功能的影响。 NHE1 敲除小鼠的 VSMC 和 EC 中的 Na+/H+ 交换活性被消除，但在存在 CO2/HCO3 的情况下，稳态 pHi 不受影响。 NHE1 敲除小鼠的动脉主动张力比野生型小鼠小 30%，介质厚度也同样减少。每单位动脉长度的 VSMC 数量没有变化，而单个 VSMC 的体积和横截面积则减少。介质压力、每个 VSMC 横截面积的力产生和 VSMC Ca2+ 反应不受影响。 NHE1 敲除小鼠的血压比野生型小鼠低 25 mmHg。省略 CO2/HCO3 导致 NHE1 敲除小鼠（0.3-0.6 pH 单位）的 VSMC 和 EC 酸化程度明显高于野生型（0.02-0.1 pH 单位）小鼠。消除 NHE1 敲除小鼠中 CO2/HCO3 抑制的乙酰胆碱诱导的 NO 介导的动脉松弛，但野生型小鼠则不然。在没有 CO2/HCO3- 的情况下，NHE1 敲除小鼠的 NO 合酶和 rho 激酶抑制对去甲肾上腺素诱导的动脉收缩的影响小于野生型小鼠，而 EC Ca2+ 对乙酰胆碱的反应、VSMC Ca2+ 对去甲肾上腺素的反应以及对 S-亚硝基-N-乙酰青霉胺的血管舒张作用不受影响。总之，NHE1 介导 EC 和 VSMC 中的 Na+/H+ 交换。在生理条件下，VSMC依赖性机制的CO2/HCO3-掩盖了NHE1的pHi调节功能。 NHE1 敲除会导致肌萎缩、动脉张力降低和血压降低。在酸性 pHi 下，NO 介导的血管舒张作用和 rho 激酶依赖性 VSMC Ca2+ 敏感性降低。
Acid-base transport in the vascular wall remains incompletely understood. Here, we investigated (a) implications of Na+/H+ exchanger NHE1 knockout for vascular smooth muscle (VSMC) and endothelial cell (EC) pHi regulation, mesenteric artery morphology, vasomotor function and blood pressure regulation, and (b) consequences of sustained EC and VSMC acidification for vasomotor function. Na+/H+ exchange activity was abolished in VSMCs and ECs from NHE1 knockout mice, but with CO2/HCO3-present, steady-state pHi was unaffected. Active tension was 30% smaller in arteries from NHE1 knockout than wild-type mice, and media thickness equally reduced. Number of VSMCs per unit artery length was unchanged whereas volume and cross-sectional area of individual VSMCs were reduced. Media stress, force production per VSMC cross-sectional area and VSMC Ca2+ responses were unaffected. Blood pressure was 25 mmHg lower in NHE1 knockout than wild-typemice. Omission of CO2/HCO3caused VSMCs and ECs to acidify substantially more in NHE1 knockout (0.3-0.6 pH-units) than wild-type (0.02-0.1 pH units) mice. Removing CO2/HCO3-inhibited acetylcholine-induced NO-mediated relaxations in arteries from NHE1 knockout but not wild-type mice. Without CO2/HCO3-, effects of NO synthase and rho kinase inhibition on noradrenaline-induced contractions were smaller in arteries from NHE1 knockout than wild-type mice whereas the EC Ca2+ response to acetylcholine, VSMC Ca2+ response to noradrenaline and vasorelaxation to S-nitroso-N-acetylpenicillaminewere unaffected. In conclusion, NHE1mediates the Na+/H+ exchange in ECs and VSMCs. Under physiological conditions, CO2/HCO3-- of VSMCdependent mechanisms mask the pHi-regulatory function of NHE1. NHE1 knockout causes hypotrophys, reduced artery tension and lower blood pressure. At acidic pHi, NO-mediated vasorelaxation and rho kinase-dependent VSMC Ca2+ sensitivity are reduced.