title: Endothelium-Derived C-Type Natriuretic Peptide Contributes to Blood Pressure Regulation by Maintaining Endothelial Integrity.
abstract: 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.
authors.affiliation: 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).
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakao
authors.affiliation: 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). kuwa@kuhp.kyoto-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: 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).
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.affiliation: 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).
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: 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).
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: 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).
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.affiliation: 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).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.affiliation: 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).
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Yamada
authors.affiliation: 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).
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: 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).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.affiliation: 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).
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nagai-Okatani
authors.affiliation: 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).
authors.forename: Naoto
authors.initials: N
authors.lastname: Minamino
authors.affiliation: 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).
authors.forename: Yoko M
authors.initials: YM
authors.lastname: Nakao
authors.affiliation: 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).
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.affiliation: 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).
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.affiliation: 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).
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.affiliation: 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).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: 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).
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.affiliation: 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).
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000097:blood* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology*; D020098:Natriuretic Peptide, C-Type / Q000097:blood*; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation
chemical_list: D020098:Natriuretic Peptide, C-Type
keywords: C-type natriuretic peptide; blood pressure; endothelial function; endothelin; endothelium; guanylyl cyclase-B