Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland.
Department of Physical Education, Shaanxi Normal University, Xi'an, Shaanxi, China.
Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H221-H237. doi: 10.1152/ajpheart.00487.2020. Epub 2020 Oct 30.
Arterial smooth muscle Na/Ca exchanger-1 (SM-NCX1) promotes vasoconstriction or vasodilation by mediating, respectively, Ca influx or efflux. In vivo, SM-NCX1 mediates net Ca influx to help maintain myogenic tone (MT) and neuronally activated constriction. SM-NCX1-TG (overexpressing transgenic) mice have increased MT and mean blood pressure (MBP; +13.5 mmHg); SM-NCX1-KO (knockout) mice have reduced MT and MBP (-11.1 mmHg). Endothelium-dependent vasodilation (EDV) is often impaired in hypertension. We tested whether genetically engineered SM-NCX1 expression and consequent BP changes similarly alter EDV. Isolated, pressurized mesenteric resistance arteries with MT from SM-NCX1-TG and conditional SM-NCX1-KO mice, and femoral arteries in vivo from TG mice were studied. Acetylcholine (ACh)-dilated TG arteries with MT slightly more than control or KO arteries, implying that SM-NCX1 overexpression does not impair EDV. In preconstricted KO, but not TG mouse arteries, however, ACh- and bradykinin-triggered vasodilation was markedly attenuated. To circumvent the endothelium, phenylephrine-constricted resistance arteries were tested with Na-nitroprusside [SNP; nitric oxide (NO) donor] and cGMP. This endothelium-independent vasodilation was augmented in TG but attenuated in KO arteries that lack NCX1-mediated Ca clearance. Baseline cytosolic Ca ([Ca]) was elevated in TG femoral arteries in vivo, supporting the high BP; furthermore, SNP-triggered [Ca] decline and vasodilation were augmented as NO and cGMP promote myocyte polarization thereby enhancing NCX1-mediated Ca efflux. The TG mouse data indicate that BP elevation does not attenuate endothelium-dependent vasodilation. Thus, in essential hypertension and many models the endothelial impairment that supports the hypertension apparently is not triggered by BP elevation but by extravascular mechanisms. Endothelium-dependent, ACh-induced vasodilation (EDV) is attenuated, and arterial myocyte Na/Ca exchangers (NCX1) are upregulated in many forms of hypertension. Surprisingly, mildly hypertensive smooth muscle-specific (SM)-NCX1 transgenic mice exhibited modestly enhanced EDV and augmented endothelium-independent vasodilation (EIV). Conversely, mildly hypotensive SM-NCX1-knockout mice had greatly attenuated EIV. These adaptations help compensate for NCX1 expression-induced alterations in cytosolic Ca and blood pressure (BP) and belie the view that elevated BP, itself, causes the endothelial dysregulation in hypertension.
动脉平滑肌钠/钙交换器-1（SM-NCX1）通过介导 Ca 内流或外流，分别促进血管收缩或舒张。在体内，SM-NCX1 介导净 Ca 内流，有助于维持肌源性张力（MT）和神经元激活收缩。SM-NCX1-TG（过表达转基因）小鼠具有更高的 MT 和平均血压（MBP；+13.5mmHg）；SM-NCX1-KO（敲除）小鼠具有更低的 MT 和 MBP（-11.1mmHg）。高血压时，内皮依赖性血管舒张（EDV）通常受损。我们测试了基因工程 SM-NCX1 表达和由此导致的血压变化是否同样改变 EDV。来自 SM-NCX1-TG 和条件性 SM-NCX1-KO 小鼠的分离、加压肠系膜阻力动脉和 TG 小鼠体内的股动脉进行了研究。乙酰胆碱（ACh）扩张的 TG 动脉的 MT 略高于对照或 KO 动脉，这意味着 SM-NCX1 过表达不会损害 EDV。然而，在预收缩的 KO 动脉中，而不是 TG 动脉中，ACh 和缓激肽触发的血管舒张明显减弱。为了绕过内皮细胞，用硝普钠[SNP；一氧化氮（NO）供体]和 cGMP 测试了去甲肾上腺素收缩的阻力动脉。这种内皮细胞独立的血管舒张在 TG 中增强，但在缺乏 NCX1 介导的 Ca 清除的 KO 动脉中减弱。体内 TG 股动脉的基础细胞浆 Ca（[Ca]）升高，支持高 BP；此外，SNP 触发的[Ca]下降和血管舒张增强，因为 NO 和 cGMP 促进肌细胞极化，从而增强 NCX1 介导的 Ca 外流。TG 小鼠的数据表明，BP 升高不会减弱内皮依赖性血管舒张。因此，在原发性高血压和许多模型中，支持高血压的内皮损伤显然不是由血压升高引起的，而是由血管外机制引起的。在许多形式的高血压中，内皮依赖性、乙酰胆碱诱导的血管舒张（EDV）减弱，动脉平滑肌钠/钙交换器（NCX1）上调。令人惊讶的是，轻度高血压的平滑肌特异性（SM）-NCX1 转基因小鼠表现出适度增强的 EDV 和增强的内皮细胞独立的血管舒张（EIV）。相反，轻度低血压的 SM-NCX1 敲除小鼠的 EIV 大大减弱。这些适应性有助于补偿 NCX1 表达诱导的细胞浆 Ca 和血压（BP）变化，并证明了升高的 BP 本身会导致高血压中的内皮失调的观点是错误的。
