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


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.
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.
Petteri
P
Rinne
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.).
Ari
A
Ahola-Olli
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.).
Salla
S
Nuutinen
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.).
Emilia
E
Koskinen
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.).
Katja
K
Kaipio
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.).
Kim
K
Eerola
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.).
Markus
M
Juonala
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.).
Mika
M
Kähönen
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.).
Terho
T
Lehtimäki
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.).
Olli T
OT
Raitakari
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.).
Eriika
E
Savontaus
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure; D003094:Collagen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D059289:Vascular Stiffness; D014661:Vasoconstriction; D014664:Vasodilation
D044102:Receptor, Melanocortin, Type 1; D009569:Nitric Oxide; D003094:Collagen
inflammation; melanocortins; nitric oxide; vasodilatation