Therapies that enhance pulmonary vascular NO-signaling in the neonate

There are several pulmonary hypertensive diseases that affect the neonatal population, including persistent pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). While the indication for inhaled nitric oxide (iNO) use is for late-preterm and term neonates with PPHN, there is a suboptimal response to this pulmonary vasodilator in ~40% of patients. Additionally, there are no FDA-approved treatments for BPD-associated PH or for preterm infants with PH. Therefore, investigating mechanisms that alter the nitric oxide-signaling pathway has been at the forefront of pulmonary vascular biology research. In this review, we will discuss the various mechanistic pathways that have been targets in neonatal PH, including NO precursors, soluble guanylate cyclase modulators, phosphodiesterase inhibitors and antioxidants. We will review their role in enhancing NO-signaling at the bench, in animal models, as well as highlight their role in the treatment of neonates with PH. •Limited pharmacotherapies are available for neonates with pulmonary hypertension (PH).•Inhaled NO is the only FDA-approved therapy for persistent PH of the newborn (PPHN), but morbidity and mortality persist.•~40% of patients with PPHN do not respond to inhaled NO therapy.•No FDA-approved therapies exist for bronchopulmonary dysplasia (BPD)-associated PH.•NO precursors, sGC, PDEs, and oxidant pathways, are research targets that can enhance NO signaling for potential PH therapy.