title: 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.forename: Amie J
authors.initials: AJ
authors.lastname: Moyes
authors.forename: Rayomand S
authors.initials: RS
authors.lastname: Khambata
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Villar
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Bubb
authors.forename: Reshma S
authors.initials: RS
authors.lastname: Baliga
authors.forename: Natalie G
authors.initials: NG
authors.lastname: Lumsden
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gane
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Rebstock
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Worthington
authors.forename: Michela I
authors.initials: MI
authors.lastname: Simone
authors.forename: Filipa
authors.initials: F
authors.lastname: Mota
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivilla
authors.forename: Susana
authors.initials: S
authors.lastname: Vallejo
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sánchez Ferrer
authors.forename: Snezana
authors.initials: S
authors.lastname: Djordjevic
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: MacAllister
authors.forename: David L
authors.initials: DL
authors.lastname: Selwood
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
mesh_terms: D000818:Animals; D001014:Aortic Aneurysm / Q000209:etiology; D050197:Atherosclerosis / Q000209:etiology; D001792:Blood Platelets / Q000502:physiology; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006706:Homeostasis; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000502:physiology*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects
chemical_list: D020098:Natriuretic Peptide, C-Type; D002118:Calcium
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