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

• Published in: Circulation (New York, N.Y.) Vol. 139; no. 13; pp. 1612 - 1628
• Main Authors: Bubb, Kristen J., Aubdool, Aisah A., Moyes, Amie J., Lewis, Sarah, Drayton, Jonathan P., Tang, Owen, Mehta, Vedanta, Zachary, Ian C., Abraham, David J., Tsui, Janice, Hobbs, Adrian J.
• Format: Journal Article
• Language: English
• Published: United States by the American College of Cardiology Foundation and the American Heart Association, Inc 26-03-2019
• Subjects: Animals; Cell Hypoxia; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Mice; Mice, Knockout; Natriuretic Peptide, C-Type - genetics; Natriuretic Peptide, C-Type - metabolism; Neovascularization, Physiologic; Signal Transduction; Vascular Remodeling; endothelium; peripheral arterial disease; natriuretic peptide, C-type; vascular remodeling; ischemia; neovascularization, physiologic
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.118.036344

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.