2. Academic Validation
  3. Endothelial C-type natriuretic peptide/guanylyl cyclase-B signaling prevents pulmonary arterial hypertension

Endothelial C-type natriuretic peptide/guanylyl cyclase-B signaling prevents pulmonary arterial hypertension

  • Nat Commun. 2026 Mar 17;17(1):2331. doi: 10.1038/s41467-026-70139-2.
Hiromu Yanagisawa 1,  Koichiro Kuwahara 2,  Yasuaki Nakagawa 3 4,  Kenji Moriuchi 1 5,  Hideyuki Kinoshita 1,  Hideaki Inazumi 1,  Takahiko Kanamori 1,  Toshio Nishikimi 1 6,  Miku Oya 7,  Kazuhiro Nakao 5,  Yohei Ueda 8,  Daisuke Nakamura 9,  Kimihiro Shimizu 9,  Koji Yoshie 7,  Satona Tanaka 10,  Daisuke Nakajima 10,  Ichiro Sakanoue 10,  Akihiro Yasoda 11,  Kazuwa Nakao 12,  Takeshi Kimura 1 13,  Koh Ono 1
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 2 Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan. [email protected].
  • 3 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].
  • 4 Center for Preventive Medicine and Division of Cardiovascular Medicine, Cardiovascular Center, Medical Research Institute KITANO HOSPITAL PIIF Tazuke-kofukai, Osaka, Japan. [email protected].
  • 5 National Cerebral and Cardiovascular Research Center Hospital, Suita, Japan.
  • 6 Wakakusa-Tatsuma Rehabilitation Hospital, Daito, Japan.
  • 7 Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
  • 8 Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 9 Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
  • 10 Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.
  • 11 National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  • 12 Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 13 Hirakata Kohsai Hospital, Hirakata, Japan.
PMID: 41844596 DOI: 10.1038/s41467-026-70139-2
Abstract

C-type natriuretic peptide (CNP) is released from endothelial cells and acts as an autocrine/paracrine mediator, regulating systemic blood pressure and vascular remodeling via guanylyl cyclase-B (GC-B) and natriuretic peptide receptor-C. We investigate the impact of vascular CNP/GC-B signaling on the development of pulmonary arterial hypertension (PAH). Mice developing pulmonary hypertension (PH) show reduced pulmonary NPPC and NPR2 expression than mice without PH. Similarly, endothelial cells (EC) from patients with idiopathic PAH exhibit lower NPPC and NPR2 expression than control EC. EC-specific CNP or GC-B conditional knockout (CNP ecKO or GC-B ecKO) mice, but not smooth muscle cell-specific GC-B conditional knockout (GC-B smcKO) mice, show more severe PH and greater expression of Edn1, Il6, Ccl2 and Tgfb1 mRNAs than their genetic controls in PAH models. CNP suppresses hypoxia-induced increases in expression of these mRNAs and restored SMAD2/3-SMAD1/5/9 balance in cultured human pulmonary arterial EC. Moreover, CNP administration prevents PH in genetic control and GC-B-smcKO mice but not in GC-B ecKO mice. CNP administration also has therapeutic effects against Sugen5416-hypoxia PAH models as well as additive benefits with established therapies. Endothelial CNP/GC-B signaling thus exerts pivotal preventative effects against development of PH, suggesting the therapeutic potential of CNP for PAH.

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