Background: Lower concentrations of undercarboxylated OC (ucOC) are associated with a higher risk for cardiovascular disease and a higher systolic and diastolic blood pressure. We tested the hypotheses that (i) ucOC is present in diseased blood vessels and red blood cells (RBC), (ii) the Class C G protein-coupled receptor (GPCR)6A, the likely receptor of ucOC in other tissues, is also the receptor in blood vessels and RBCs, and (iii) ucOC treatment dilates diseased vessels.

Methods: Radial artery segments were collected from patients undergoing coronary artery bypass surgery (n=6) and conduit (iliac) and resistance (renal interlobar) vessels from New Zealand white rabbits fed an atherogenic diet or a normal chow diet (as control) for 4 weeks. Immunohistochemistry was used to determine ucOC and GPRC6A localization and Proximity Ligation Assay for ucOC/GPRC6A localization. Organ bath techniques, rabbit studies, were used to determine vasodilatory effects of ucOC.

Results: ucOC and GPRC6A are expressed in human and rabbit blood vessels and RBCs. In RBC, but not blood vessels, ucOC and GPRC6A were in close proximity (<40nM) indicating binding. In both diseased and controls arteries ucOC induced dose dependent vasodilatations, however, in iliac arteries dilations were significantly greater in diseased compared to control arteries (15ng/mL ucOC 43.6±14.8% versus 9.8±6.9% p<0.05, respectively) while in resistance arteries (renal interlobar) dilation was significantly attenuated in diseased compared to control (15ng/mL ucOC 17.9±10.6% versus 47.8±3.5% p<0.05, respectively). In both arteries the response to ucOC was independent of nitric oxide (NO)-mediated dilatation.

Conclusions: ucOC and GPRC6A are expressed in human and rabbit diseased artery and in RBCs. ucOC treatment causes blood vessels dilatation independent of NO, however, the magnitude of dilatation is vessel specific with greater response in conduit vessels. ucOC can be considered as a future novel treatment for vascular dysfunction.