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Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1678-86. doi: 10.1161/ATVBAHA.114.305064. Epub 2015 Apr 30.

Deficiency in Melanocortin 1 Receptor Signaling Predisposes to Vascular Endothelial Dysfunction and Increased Arterial Stiffness in Mice and Humans.

Author information

1
From the Department of Pharmacology, Drug Development and Pharmaceutics (P.R., S.N., E.K., K.E.,E.S.), the Research Centre of Applied and Preventive Cardiovascular Medicine (A.A-O., O.T.R.), and Department of Pathology (K.K), University of Turku, Turku, Finland; Division of Medicine (M.J.), Department of Clinical Physiology and Nuclear Medicine (O.T.R), and the Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland; Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland (M.K.); Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland (T.L.); and Murdoch Children's Research Institute, Parkville, Victoria, Australia (M.J.). pperin@utu.fi.
2
From the Department of Pharmacology, Drug Development and Pharmaceutics (P.R., S.N., E.K., K.E.,E.S.), the Research Centre of Applied and Preventive Cardiovascular Medicine (A.A-O., O.T.R.), and Department of Pathology (K.K), University of Turku, Turku, Finland; Division of Medicine (M.J.), Department of Clinical Physiology and Nuclear Medicine (O.T.R), and the Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland; Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland (M.K.); Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland (T.L.); and Murdoch Children's Research Institute, Parkville, Victoria, Australia (M.J.).

Abstract

OBJECTIVE:

The melanocortin 1 receptor (MC1-R) is expressed by vascular endothelial cells and shown to enhance nitric oxide (NO) availability and vasodilator function on pharmacological stimulation. However, the physiological role of MC1-R in the endothelium and its contribution to vascular homeostasis remain unresolved. We investigated whether a lack of functional MC1-R signaling carries a phenotype with predisposition to vascular abnormalities.

APPROACH AND RESULTS:

Recessive yellow mice (MC1R(e/e)), deficient in MC1-R signaling, and their wild-type littermates were studied for morphology and functional characteristics of the aorta. MC1R(e/e) mice showed increased collagen deposition and arterial stiffness accompanied by an elevation in pulse pressure. Contractile capacity and NO-dependent vasodilatation were impaired in the aorta of MC1R(e/e) mice supported by findings of decreased NO availability. These mice also displayed elevated levels of systemic and local cytokines. Exposing the mice to high-sodium diet or acute endotoxemia revealed increased susceptibility to inflammation-driven vascular dysfunction. Finally, we investigated whether a similar phenotype can be found in healthy human subjects carrying variant MC1-R alleles known to attenuate receptor function. In a longitudinal analysis of 2001 subjects with genotype and ultrasound data (The Cardiovascular Risk in Young Finns Study), weak MC1-R function was associated with lower flow-mediated dilatation response of the brachial artery and increased carotid artery stiffness.

CONCLUSIONS:

The present study demonstrates that deficiency in MC1-R signaling is associated with increased arterial stiffness and impairment in endothelium-dependent vasodilatation, suggesting a physiological role for MC1-R in the regulation of arterial tone.

KEYWORDS:

inflammation; melanocortins; nitric oxide; vasodilatation

PMID:
25931512
DOI:
10.1161/ATVBAHA.114.305064
[Indexed for MEDLINE]

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