Sildenafil Improves Pulmonary Vascular Remodeling in a Rat Model of Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by pulmonary arterial remodeling mainly because of apoptosis resistance and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Sildenafil is a phosphodiesterase-5 inhibitor. Some reports have shown that sildenafil exerts protective effects against PPHN. However, the function of sildenafil in PPHN and the underlying molecular mechanisms is not clear. Here, we revealed that sildenafil effectively suppressed hypoxia-induced PASMC proliferation and apoptosis inhibition (P < 0.05). Also, sildenafil obviously reduced ventricular hypertrophy, and inhibited pulmonary vascular remodeling in the PPHN model (P < 0.05). Moreover, sildenafil treatment significantly attenuated the induction of Notch3 and Hes1 induced by hypoxia treatment (P < 0.05). Furthermore, overexpression of Notch3 abolished the reduction of PASMC proliferation and promotion of PASMC apoptosis induced by sildenafil under hypoxia (P < 0.05), whereas knockdown of Notch3 had an opposite effect (P < 0.05). Together, our study demonstrates that sildenafil shows a potential benefit against the development of PPHN by inhibiting Notch3 signaling, providing a strategy for treating PPHN in the future.