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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Blood Pressure
  • Collagen / metabolism
  • Endothelium, Vascular / metabolism*
  • Humans
  • Inflammation / metabolism
  • Mice
  • Nitric Oxide / metabolism
  • Receptor, Melanocortin, Type 1 / metabolism*
  • Signal Transduction
  • Vascular Stiffness*
  • Vasoconstriction
  • Vasodilation


  • Receptor, Melanocortin, Type 1
  • Nitric Oxide
  • Collagen