Endothelial C-Type Natriuretic Peptide Is a Critical Regulator of Angiogenesis and Vascular Remodeling
Authors: Vedanta Mehta
Aisah A Aubdool
Amie J Moyes
David J Abraham
Jonathan P Drayton
Owen Tang
Adrian J Hobbs
Sarah Lewis
Janice Tsui
Ian C Zachary
Kristen J Bubb
Journal: Circulation (2019)
Discipline: CLINICAL MEDICINE
Keywords: endothelium; ischemia; natriuretic peptide, C-type; neovascularization, physiologic; peripheral arterial disease
Affiliations: William Harvey Research Institute, Barts &amp; The London School of Medicine &amp; Dentistry, Queen Mary University of London, UK (K.J.B., A.A.A., A.J.M., J.P.D., A.J.H.)., Centre for Rheumatology and Connective Tissue Diseases, University College London Medical School, Royal Free Campus, UK (S.L., D.J.A., J.T.)., University of Sydney, Kolling Institute of Medical Research, St Leonards, Australia (K.J.B., O.T.)., Centre for Cardiovascular Biology and Medicine, Division of Medicine, University College London, UK (V.M., I.C.Z.).

Abstract:  Background: Angiogenesis and vascular remodeling are complementary, innate responses to ischemic cardiovascular events, including peripheral artery disease 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 and aortic rings isolated from wild-type, endothelium-specific CNP-/-, global natriuretic peptide receptor (NPR)-B-/- and NPR-C-/- animals, and human umbilical vein endothelial cells. These studies were complemented by in vivo investigation of neovascularization and vascular remodeling after ischemia or vessel injury, and CNP/NPR-C expression and localization in tissue from patients with peripheral artery disease. 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 pulmonary microvascular endothelial cells, human umbilical vein endothelial cells, and isolated vessels ex vivo. Angiogenesis and remodeling are impaired in vivo in endothelium-specific CNP-/- 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 proangiogenic effect of CNP/NPR-C is dependent on activation of Gi, ERK1/2, and phosphoinositide 3-kinase γ/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 peripheral artery disease and ischemic cardiovascular disorders. 

Retracted: No

PubPeer comments:
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