Sildenafil is a phosphodiesterase 5 and 6 (PDE5, PDE6) inhibitor that is clinically used to treat erectile dysfunction and pulmonary arterial hypertension. Sildenafil exhibits antihypertensive (through vasodilatory action), antioxidative, and anti-inflammatory activities. In mouse models of sickle cell anemia, sildenafil promotes eNOS activation and inhibits NADPH oxidase, decreasing oxidative stress. In other animal models, sildenafil decreases Iba-1, IFN-γ, and IL-1β levels and increases glutathione levels, improving myelin structure. This compound also decreases iNOS, TNF-α, and caspase-3 expression in vivo. Additionally, sildenafil restores phosphorylation of smad1/5 and expression of inhibitor of DNA binding protein 1 in animals, preventing vascular remodeling and the development of pulmonary hypertension and potentiating bone morphogenetic protein signaling.