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.
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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.
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