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 1

Development and characterization of an endothelium-specific CNP knockout mouse.

Options: View larger image (or click on image) Download as PowerPoint
Development and characterization of an endothelium-specific CNP knockout...
Cell-specific deletion of the CNP gene was achieved by flanking exons 1 and 2 of the CNP (Nppc) gene with LoxP sites (A). Flippase recognition target (FRT) sites were used to permit efficient removal of the neomycin cassette by breeding chimeric mice with ubiquitous Flpe-expressing animals, resulting in the generation of Nppc+/fl offspring. Nppcfl/fl animals were then crossed with a mouse in which expression of Cre recombinase is driven by an endothelial-specific promoter/enhancer associated with the angiopoietin Tie2 receptor. Heterozygous animals at the Nppc locus that expressed the Tie2 transgene (Tie2-Cre Nppc+/fl) were used as breeding pairs to generate ecCNP KO and corresponding WT (Tie2-Cre Nppc+/+) littermate controls. Analysis of the DNA from these animals confirmed generation of the 6 possible genotypes (B). qPCR analysis of CNP mRNA from different tissues established that the CNP gene had been deleted selectively from vascular endothelial cells (C). Measurement of plasma CNP concentrations under basal conditions and following administration of LPS (12.5 mg/kg; i.p.; 12 h) confirmed that peptide levels were significantly reduced in ecCNP KO versus WT animals (D). Data are represented as the mean ± SEM. n = 5. ***P < 0.001, significantly different from corresponding WT littermates.