Endothelial natriuretic peptide receptor 1 play crucial role for acute and chronic blood pressure regulation by atrial natriuretic peptide
Endothelial natriuretic peptide receptor 1 play crucial role for acute and chronic blood pressure regulation by atrial natriuretic peptide
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内皮利钠肽受体1在心房利钠肽调节急性和慢性血压中发挥关键作用
DOI：
10.1161/hypertensionaha.121.18114
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发表时间：
2022
期刊：
影响因子：
8.3
通讯作者：
Nishimura H.
中科院分区：
文献类型：
--
作者：
Tokudome T;Otani K;Mao Y;Jensen LJ;Arai Y;Miyazaki T;Sonobe T;Pearson JT;Osaki T;Minamino N;Ishida J;Fukamizu A;Kawakami H;Onozuka D;Nishimura K;Miyazato M;Nishimura H.
心钠素(ANP)通过心钠素受体1(NPR1)作用，引起低血压。这种低血压被认为是由于ANP通过NPR1在血管系统中诱导血管扩张；然而，其潜在的机制尚不清楚。方法和结果大鼠组织免疫组织化学分析显示，NPR1在小动脉和小动脉内皮细胞和平滑肌细胞中大量表达。静脉注射ANP可显著降低野生型小鼠的收缩压。ANP还能显著降低Npr1基因敲除小鼠的收缩压，但不能降低内皮细胞Npr1基因敲除小鼠的血压。此外，ANP显著降低NOS3基因敲除小鼠的收缩压。在人脐静脉内皮细胞中，ANP处理不影响一氧化氮的产生或细胞内钙离子浓度，但它确实使细胞超极化。心钠素诱导的人脐静脉内皮细胞超极化可被几种钾通道阻滞剂抑制，也可被G蛋白α亚基中的GTP酶激活蛋白RGS2阻断。ANP可增加人脐静脉内皮细胞Rgs2mRNA的表达，但不能降低Rgs2基因敲除小鼠的收缩压。结论血管内皮细胞NPR1在ANP介导的血压调节中发挥重要作用，其机制可能是急性期依赖RGS2，慢性期不依赖RGS2。
BackgroundANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP.Methods and ResultsImmunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell–specificNpr1–knockout mice but not in endothelial cell–specificNpr1–knockout mice. Moreover, ANP significantly lowered systolic blood pressure inNos3-knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca2+concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increasedRgs2mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure inRgs2-knockout mice. Endothelial cell–specificNpr1-overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography.ConclusionsTogether, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.