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.
View: Text | PDF
Research Article Vascular biology

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

×

Figure 2

Endothelial dysfunction and hypertension in ecCNP KO mice.

Options: View larger image (or click on image) Download as PowerPoint
Endothelial dysfunction and hypertension in ecCNP KO mice. Endothelium-d...
Endothelium-dependent relaxation to ACh in isolated aorta and mesenteric artery of male ecCNP KO animals was unaltered in comparison with that of littermate controls (A and B). In contrast, there was a small reduction in maximal ACh relaxation in the aorta (E) and significant decrease in potency to ACh in the mesenteric arteries (F) of female ecCNP KO animals. MABP of male (C and D) and female (G and H) WT and ecCNP KO animals paralleled the in vitro vascular reactivity with a hypertensive phenotype only apparent in females; heterozygous ecCNP animals exhibited an intermediate phenotype (H). An analogous endothelial dysfunction (J) and hypertensive phenotype (K) was apparent in female NPR-C KO animals, whereas male NPR-C KO mice maintained normal endothelial function (I) and exhibited a mild hypotensive phenotype (K). CNP relaxed human mesenteric resistance arteries in a concentration-dependent manner and was sensitive to the NPR-C antagonist M372049 and high [K+] (L). Vasorelaxant responses in B, F, I, J, and L were obtained in the presence of L-NAME and indomethacin. Data are represented as the mean ± SEM. n = 6 for isolated vessel studies, n = 8 for the in vivo MABP studies. ***P < 0.001, significantly different from WT littermates; ###P < 0.01, significantly different from heterozygote littermates.