Nitric oxide (NO)-mediated vasodilatation is a fundamental response of vasculature, however, regulation of NO signaling pathway on resistance vessels in the older adult with hypertension is still unclear. The 16-week-spontaneously hypertensive rats (SHR), the 18-month-SHR (OldSHR), and the age-matched Wistar-Kyoto rats were used to study the changes of mesenteric resistance artery dilatation caused by sodium nitroprusside (SNP). After pre-vasoconstriction by norepinephrine (NE), the response of endothelium-denuded mesenteric artery ring to SNP was observed, and the changes in vascular response after pharmacological interventions of key nodes in the NO/sGC/cGMP/PKG1α signaling pathway were observed as well. RNA sequencing and functional enrichment analyses were used to provide information for conducting validation experiments. Vasodilation of NO in OldSHR was decreased, which significantly correlated with the reduction of PKG-mediated effect. Functional enrichment analysis of RNA sequencing showed that genes encoding important proteins such as sGC and MYPT1 (protein phosphatase 1 regulatory subunit 12A) were downregulated in OldSHR. Molecular biology validation results showed that mRNA expression of both α and β subunits of sGC were reduced, while mRNA and protein expression of PKG1α were reduced in OldSHR. More importantly, the expression of MYPT1 and pS668-MYPT1 was significantly reduced in OldSHR, even under the treatment of SNP. The experiment also revealed an enhanced cAMP system in vasodilation in hypertension, while this function was completely lost in the OldSHR. Therefore, an NO-mediated decrease in vascular smooth muscle relaxation was found in the OldSHR. The dysfunction in cGMP-PKG signaling, in particular, decreased pS668-MYPT1 was mechanistically involved.

中文翻译：

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MYPT1 的降低对于老年自发性高血压大鼠肠系膜动脉中 NO 介导的血管舒张受损至关重要

一氧化氮（NO）介导的血管舒张是脉管系统的基本反应，然而，在老年高血压患者中，NO信号通路对阻力血管的调节仍不清楚。采用16周自发性高血压大鼠(SHR)、18个月自发性高血压大鼠(OldSHR)和年龄匹配的Wistar-Kyoto大鼠研究硝普钠(SNP)引起肠系膜阻力动脉扩张的变化。去甲肾上腺素（NE）预缩血管后，观察去内皮肠系膜动脉环对SNP的反应，观察NO/sGC/cGMP/PKG1α信号通路关键节点药物干预后血管反应的变化为好。RNA测序和功能富集分析用于为进行验证实验提供信息。OldSHR 中 NO 的血管舒张作用降低，这与 PKG 介导的作用降低显着相关。RNA测序的功能富集分析表明，编码重要蛋白质的基因如sGC和MYPT1（蛋白磷酸酶1调节亚基12A）在OldSHR中下调。分子生物学验证结果显示，sGC α 和 β 亚基的 mRNA 表达均降低，而 OldSHR 中 PKG1α 的 mRNA 和蛋白表达降低。更重要的是，即使在 SNP 处理下，在 OldSHR 中 MYPT1 和 pS668-MYPT1 的表达也显着降低。该实验还揭示了高血压患者血管舒张中的 cAMP 系统增强，而此功能在 OldSHR 中完全丧失。因此，在 OldSHR 中发现 NO 介导的血管平滑肌松弛减少。