Vericiguat restores estrogen-like metabolic benefits without uterine trophic effects in an obese ovariectomized rat model and increases cardiac PKG-I expression

The soluble guanylate cyclase–cyclic guanosine monophosphate/protein kinase G (sGC–cGMP/PKG) pathway plays an important role in metabolic homeostasis and is disrupted in obesity and estrogen deficiency. Given the limitations of estrogen therapy, this study investigated whether vericiguat (VER), an sGC stimulator, could mimic the metabolic effects of 17β-estradiol (E2) in obese ovariectomized rats. Female Wistar rats were assigned to sham-operated or ovariectomized (OVX) groups. OVX rats were fed a standard diet (SD) or a high-fat diet (HFD; 60% kcal from fat) for four months to induce obesity, and diets were maintained during the subsequent four-week treatment period. Rats received low-dose (0.3 mg/kg) or high-dose (1 mg/kg) VER, E2, or both. OVX increased body weight, body mass index (BMI), visceral fat mass percentage (VFM%), adipocyte area, blood glucose, and impaired lipid profile while reducing PKG-I expression and uterine weight; HFD exacerbated these changes. VER, alone or combined with E2, significantly improved body weight, BMI, VFM%, adipocyte area, blood glucose, lipid profile, and cardiac PKG-I expression. Unlike E2, VER did not increase uterine weight or induce uterotrophic histopathological changes. These findings suggest that VER may recapitulate estrogen’s metabolic protection without uterine trophic effects in obese ovariectomized rats.