Nakao Kazuhiro, Kuwahara Koichiro, Nishikimi Toshio, Nakagawa Yasuaki, Kinoshita Hideyuki, Minami Takeya, Kuwabara Yoshihiro, Yamada Chinatsu, Yamada Yuko, Tokudome Takeshi, Nagai-Okatani Chiaki, Minamino Naoto, Nakao Yoko M, Yasuno Shinji, Ueshima Kenji, Sone Masakatsu, Kimura Takeshi, Kangawa Kenji, Nakao Kazuwa
From the Department of Medicine and Clinical Science (Kazuhiro Nakao, K. Kuwahara, T.N., Y.N., H.K., T.M., Y.K., C.Y., Y.Y., M.S., Kazuwa Nakao), Department of Peptide Research (Kazuhiro Nakao, Y.Y., K. Kangawa), Medical Innovation Center (Kazuwa Nakao), and Department of Cardiovascular Medicine (K. Kuwahara, T.N., Y.N., H.K., T.M., C.Y., T.K.), Kyoto University Graduate School of Medicine, Japan; Department of Biochemistry (T.T., K. Kangawa) and Department of Molecular Pharmacology (C.N.-O., N.M.), National Cerebral and Cardiovascular Center, Japan; Department of EBM Research, Institute for Advanced of Clinical and Translational Science, Kyoto University Hospital, Japan (Y.K., Y.M.N., S.Y., K.U.); and Department of Cardiovascular Medicine, Shinshu University School of Medicine, Japan (K. Kuwahara).
Hypertension. 2017 Feb;69(2):286-296. doi: 10.1161/HYPERTENSIONAHA.116.08219. Epub 2017 Jan 3.
We previously reported the secretion of C-type natriuretic peptide (CNP) from vascular endothelial cells and proposed the existence of a vascular natriuretic peptide system composed of endothelial CNP and smooth muscle guanylyl cyclase-B (GC-B), the CNP receptor, and involved in the regulation of vascular tone, remodeling, and regeneration. In this study, we assessed the functional significance of this system in the regulation of blood pressure in vivo using vascular endothelial cell-specific CNP knockout and vascular smooth muscle cell-specific GC-B knockout mice. These mice showed neither the skeletal abnormality nor the early mortality observed in systemic CNP or GC-B knockout mice. Endothelial cell-specific CNP knockout mice exhibited significantly increased blood pressures and an enhanced acute hypertensive response to nitric oxide synthetase inhibition. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in rings of mesenteric artery isolated from endothelial cell-specific CNP knockout mice. In addition, endothelin-1 gene expression was enhanced in pulmonary vascular endothelial cells from endothelial cell-specific CNP knockout mice, which also showed significantly higher plasma endothelin-1 concentrations and a greater reduction in blood pressure in response to an endothelin receptor antagonist than their control littermates. By contrast, vascular smooth muscle cell-specific GC-B knockout mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved in their isolated mesenteric arteries. Nonetheless, CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from vascular smooth muscle cell-specific GC-B knockout mice. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.
我们之前报道了血管内皮细胞分泌C型利钠肽（CNP），并提出存在一种由内皮CNP和平滑肌鸟苷酸环化酶-B（GC-B）、CNP受体组成的血管利钠肽系统，该系统参与血管张力、重塑和再生的调节。在本研究中，我们使用血管内皮细胞特异性CNP基因敲除小鼠和血管平滑肌细胞特异性GC-B基因敲除小鼠，评估了该系统在体内血压调节中的功能意义。这些小鼠既没有表现出全身CNP或GC-B基因敲除小鼠所观察到的骨骼异常，也没有出现早期死亡。血管内皮细胞特异性CNP基因敲除小鼠的血压显著升高，对一氧化氮合酶抑制的急性高血压反应增强。从血管内皮细胞特异性CNP基因敲除小鼠分离的肠系膜动脉环中，乙酰胆碱诱导的内皮依赖性血管舒张受损。此外，血管内皮细胞特异性CNP基因敲除小鼠的肺血管内皮细胞中内皮素-1基因表达增强，与同窝对照小鼠相比，其血浆内皮素-1浓度也显著更高，对内皮素受体拮抗剂的血压降低反应更大。相比之下，血管平滑肌细胞特异性GC-B基因敲除小鼠的血压与对照小鼠相似，其分离的肠系膜动脉中乙酰胆碱诱导的血管舒张得以保留。尽管如此，血管平滑肌细胞特异性GC-B基因敲除小鼠的肠系膜动脉中，CNP诱导的急性血管舒张几乎完全消失。这些结果表明，内皮源性CNP通过独立于血管平滑肌GC-B维持内皮功能，有助于血管张力和全身血压的慢性调节。
