Vericiguat rescues cyclic guanosine monophosphate production in human aortic vascular smooth muscle cells and augments vasorelaxation in aortic rings exposed to high glucose

Background:Vascular smooth muscle cell (VSMC) function relies on endothelial derived nitric oxide (NO) to stimulate cyclic guanosine monophosphate (cGMP) production through soluble guanylyl cyclase (sGC), and vasorelaxation. In inflammatory contexts like high glucose (HG), NO availability is reduced. We investigated whether vericiguat, an sGC stimulator, enhances cGMP production in HG exposed VSMCs and vasorelaxation in isolated aortic rings. Methods:Aortic VSMCs were exposed to normal glucose (NG; 4.5 mM D-glucose+25.5mM L-glucose), HG (30 mM D-glucose), or HG with 1uM vericiguat. All groups received sildenafil (1uM) and the NO donor, DETA NONOate (0.1uM). At 24h, intracellular cGMP was measured. Aortas obtained from c57BL/6 mice were exposed to HG (40mM D-glucose), HG +vericiguat, or NG (5mM D-glucose +35mM L-glucose) for 24h. The rings were pre-contracted with phenylephrine (1uM) and dose response curves to acetylcholine (Ach) constructed. Results:cGMP production in VSMCs exposed to HG was lower than in those exposed to NG but was rescued in those who also received 1uM vericiguat. In isolated mouse aortas, Ach-mediated relaxation was impaired following pre-treatment with HG, but not in the HG+vericiguat group. Conclusion:Vericiguat enhances ACh-mediated vasorelaxation and restores cGMP production in VSMCs exposed to HG. The findings support clinical studies to explore vericiguat's potential to improve VSMC function in pro-inflammatory settings.