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Endothelial C-Type Natriuretic Peptide is a Critical Regulator of Angiogenesis and Vascular Remodeling

Bubb, KJ; Aubdool, AA; Moyes, AJ; Lewis, S; Drayton, JP; Tang, O; Mehta, V; ... Hobbs, AJ; + view all (2019) Endothelial C-Type Natriuretic Peptide is a Critical Regulator of Angiogenesis and Vascular Remodeling. Circulation , 139 (13) pp. 1612-1628. 10.1161/CIRCULATIONAHA.118.036344. Green open access

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Abstract

BACKGROUND: Angiogenesis and vascular remodeling are complementary, innate responses to ischemic cardiovascular events, including peripheral artery disease (PAD) and myocardial infarction, which restore tissue blood supply and oxygenation; the endothelium plays a critical function in these intrinsic protective processes. C-type natriuretic peptide (CNP) is a fundamental endothelial signaling species that coordinates vascular homeostasis. Herein, we sought to delineate a central role for CNP in angiogenesis and vascular remodeling in response to ischemia. METHODS: The in vitro angiogenic capacity of CNP was examined in pulmonary microvascular endothelial cells (PMEC) and aortic rings isolated from wild type (WT), endothelium-specific CNP knockout (ecCNP-/-), and global natriuretic peptide receptor (NPR)-B-/- and NPR-C-/- animals, and in human umbilical vein endothelial cells (HUVEC). These studies were complemented by in vivo investigation of neovascularization and vascular remodeling following ischemia or vessel injury, and CNP/NPR-C expression & localization in tissue from patients with PAD. RESULTS: Clinical vascular ischemia is associated with reduced levels of CNP and its cognate NPR-C. Moreover, genetic or pharmacological inhibition of CNP and NPR-C, but not NPR-B, reduces the angiogenic potential of PMEC, HUVEC and isolated vessels ex vivo. Angiogenesis and remodeling are impaired in vivo in ecCNP-/- and NPR-C-/-, but not NPR-B-/-, mice; the detrimental phenotype caused by genetic deletion of endothelial CNP, but not NPR-C, can be rescued by pharmacological administration of CNP. The pro-angiogenic effect of CNP/NPR-C is dependent on activation of Gi, ERK1/2 and PI3Kγ/Akt at a molecular level. CONCLUSIONS: These data define a central (patho)physiological role for CNP in angiogenesis and vascular remodeling in response to ischemia and provide the rationale for pharmacological activation of NPR-C as an innovative approach to treating PAD and ischemic cardiovascular disorders.

Type: Article
Title: Endothelial C-Type Natriuretic Peptide is a Critical Regulator of Angiogenesis and Vascular Remodeling
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/CIRCULATIONAHA.118.036344
Publisher version: https://doi.org/10.1161/CIRCULATIONAHA.118.036344
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: arteriogenesis, natriuretic peptide receptor, vascular remodeling
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10065425
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