Endothelial C-type natriuretic peptide maintains vascular homeostasis
Amie J. Moyes, … , Amrita Ahluwalia, Adrian J. Hobbs
Amie J. Moyes, … , Amrita Ahluwalia, Adrian J. Hobbs
Published August 8, 2014
Citation Information: J Clin Invest. 2014;124(9):4039-4051. https://doi.org/10.1172/JCI74281.
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Research Article Vascular biology Article has an altmetric score of 6

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Abstract

The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor–C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.

Authors

Amie J. Moyes, Rayomand S. Khambata, Inmaculada Villar, Kristen J. Bubb, Reshma S. Baliga, Natalie G. Lumsden, Fang Xiao, Paul J. Gane, Anne-Sophie Rebstock, Roberta J. Worthington, Michela I. Simone, Filipa Mota, Fernando Rivilla, Susana Vallejo, Concepción Peiró, Carlos F. Sánchez Ferrer, Snezana Djordjevic, Mark J. Caulfield, Raymond J. MacAllister, David L. Selwood, Amrita Ahluwalia, Adrian J. Hobbs

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Figure 3

Leukocyte and platelet hyperreactivity in ecCNP KO mice.

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Leukocyte and platelet hyperreactivity in ecCNP KO mice. Basal and IL-1β...
Basal and IL-1β–stimulated (5 ng/mouse; i.p.) leukocyte rolling was significantly greater in ecCNP KO (A and B) and NPR-C KO (C and D) mice compared with WT littermates. Representative images of basal rolling are shown (E and F). Platelet aggregation in response to collagen (3 μg/ml and 10 μg/ml) and PAR4-AP (300 μM; G), basal and PAR4-AP–triggered platelet expression of P-selectin (H and I), and the level of circulating platelet-leukocyte aggregates (J) was greater in ecCNP KO mice compared with WT littermates, implying that CNP regulates platelet function (and leukocyte recruitment) via inhibition of P-selectin expression. Endothelial P-selectin expression was also significantly greater in the aorta of ecCNP KO versus WT mice (K and L). Data are represented as the mean ± SEM. n = 10 for leukocyte studies; n = 6 for platelet reactivity and flow cytometry experiments. *P < 0.05, **P < 0.01, ***P < 0.001, significantly different from WT littermates; ###P < 0.001, significantly different from heterozygote littermates. Scale bars: 50 μm (E and F); 20 μm (K).