Ribeirão Preto Medical School, University of São Paulo, Department of Pharmacology, Ribeirão Preto, SP, Brazil.
Ribeirão Preto Medical School, University of São Paulo, Department of Pharmacology, Ribeirão Preto, SP, Brazil; Laboratory of Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil.
Life Sci. 2021 May 1;272:119223. doi: 10.1016/j.lfs.2021.119223. Epub 2021 Feb 18.
Hypertension underlies endothelial dysfunction, and activation of vasorelaxation signaling with low dependence on nitric oxide (NO) represents a good alternative for vascular modulation. C-type natriuretic peptide (CNP) causes relaxation by increasing cyclic guanosine 3',5'-monophosphate (cGMP) or Gi-protein activation through its natriuretic peptide receptor-B or -C, respectively. We have hypothesized that CNP could exerts its effects and could overcome endothelial dysfunction in two kidney-one clip (2K-1C) hypertensive rat aorta. Here, we investigate the intracellular signaling involved in CNP effects in hypertension.
The 2K-1C hypertension was induced in male Wistar rats (200 g). CNP-induced vascular relaxation and cGMP production were investigated in rat thoracic aortas. The natriuretic peptide receptor-B and -C localization was evaluated by immunofluorescence. Calcium mobilization was assessed in endothelial cells from rat aortas.
CNP induced similar relaxation in normotensive and 2K-1C hypertensive rat aortas, which increased after endothelium removal. CNP-induced relaxation involved natriuretic peptide receptor-B and -C activation in 2K-1C rats. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) counter-regulated CNP-particulate GC (pGC) activation in aortas. CNP reduced endothelial calcium and increased cGMP production, which was lower in 2K-1C. CNP-induced cGMP-dependent protein kinase (PKG) and sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) activation was impaired in 2K-1C rat aorta.
Our results indicated CNP triggered relaxation through its natriuretic peptide receptor-B and -C in 2K-1C rat aortas, and that CNP-induced relaxation overcomes endothelial dysfunction in hypertension. In addition, NOS and sGC activities counter-regulate CNP-pGC activation to induce vascular relaxation.
高血压是内皮功能障碍的基础，而对一氧化氮（NO）依赖性低的血管舒张信号的激活是血管调节的一个很好的选择。C 型利钠肽（CNP）通过其利钠肽受体-B 或 -C 分别增加环鸟苷酸 3'，5'-单磷酸（cGMP）或 Gi 蛋白的激活来引起松弛。我们假设 CNP 可以在两肾一夹（2K-1C）高血压大鼠主动脉中发挥作用并克服内皮功能障碍。在这里，我们研究了 CNP 作用涉及的细胞内信号转导在高血压中的作用。
雄性 Wistar 大鼠（200g）诱导 2K-1C 高血压。在大鼠胸主动脉中研究 CNP 诱导的血管舒张和 cGMP 产生。通过免疫荧光评估利钠肽受体-B 和 -C 的定位。评估内皮细胞从大鼠主动脉中钙动员。
CNP 在正常血压和 2K-1C 高血压大鼠主动脉中诱导相似的舒张，在去除内皮后增加。CNP 诱导的舒张涉及 2K-1C 大鼠利钠肽受体-B 和 -C 的激活。一氧化氮合酶（NOS）和可溶性鸟苷酸环化酶（sGC）在主动脉中对 CNP-颗粒 GC（pGC）激活进行了反调节。CNP 降低内皮钙并增加 cGMP 产生，而在 2K-1C 中则降低。在 2K-1C 大鼠主动脉中，CNP 诱导的 cGMP 依赖性蛋白激酶（PKG）和肌浆/内质网 Ca-ATP 酶（SERCA）激活受损。
我们的结果表明，CNP 通过其利钠肽受体-B 和 -C 在 2K-1C 大鼠主动脉中触发舒张，并且 CNP 诱导的舒张克服了高血压中的内皮功能障碍。此外，NOS 和 sGC 活性可拮抗 CNP-pGC 激活以诱导血管舒张。
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