In Vivo Antihypertensive and Ex Vivo Vasodilatory Studies of Taxifolin

<b>Background</b>: Hypertension is a leading cause of cardiovascular morbidity and mortality. Taxifolin has shown cardiovascular benefits, but its antihypertensive mechanisms remain poorly defined. This study aimed to comprehensively elucidate the molecular mechanisms underlying Taxifolin's blood pressure-lowering effects by integrating network pharmacology, molecular docking, ex vivo functional studies, and in vivo validation. <b>Methods</b>: Network pharmacology and molecular docking prioritized targets. Ex vivo thoracic aortas were obtained from healthy male Sprague-Dawley (SD) rats, and rings (3-4 mm) were prepared for vasorelaxation studies. Pathway-specific inhibitors, Western blotting, and ELISA were used to investigate mechanisms. In vivo, spontaneously hypertensive rats (SHRs) received oral Taxifolin 15, 30, or 60 mg/kg once daily for 28 days; propranolol (80 mg/kg) served as the positive control. <b>Results</b>: Taxifolin produced robust vasorelaxation in endothelium-intact rings (Rmax ≈ 121%), falling to ~72% after denudation. Relaxation was attenuated by LY294002, ODQ, indomethacin, and glibenclamide. In SHR aorta, Taxifolin increased NO by ~132% and cGMP by ~1.9-fold and upregulated p-Akt and eNOS; LY294002 abolished these effects. In vivo, Taxifolin reduced systolic blood pressure by ≈60 mmHg without adverse changes in hematology, biochemistry, or body weight. <b>Conclusions</b>: Taxifolin lowers blood pressure through multiple vascular mechanisms consistent with PI3K/Akt/eNOS, NO-sGC-cGMP, COX-2/PGI₂ and calcium-handling pathways, supporting its potential as a safe antihypertensive candidate.