Intra-amniotic Sildenafil and Rosiglitazone Late in Gestation Ameliorate the Pulmonary Hypertension Phenotype in Congenital Diaphragmatic Hernia

Background: Pulmonary hypertension remains difficult to manage in congenital diaphragmatic hernia (CDH). Prenatal therapy may ameliorate postnatal pulmonary hypertension. We hypothesized that intraamniotic (IA) injection of either sildenafil, a phosphodiesterase 5 inhibitor, or rosiglitazone, a PPAR-g agonist, or both late in gestation would decrease the detrimental pulmonary vascular remodeling seen in CDH and improve peripheral pulmonary blood flow. Methods: Pregnant rats were gavaged with nitrogen on embryonic day (E) 9.5 to induce fetal CDH. Sildenafil and/or rosiglitazone were administered to each fetus via an intra-amniotic injection after laparotomy on the pregnant dam at E19.5, and fetuses delivered at E21.5. Efficacy measures were gross necropsy, histology, peripheral blood flow assessment using intra-cardiac injection of a vascular tracer after delivery, and protein expression analysis. Results: Intra-amniotic injections did not affect fetal survival, the incidence of CDH, or lung weight-tobody weight ratio in CDH fetuses. IA sildenafil injection decreased pulmonary vascular muscularization, and rosiglitazone produced an increase in peripheral pulmonary blood flow distribution. The combination of sildenafil and rosiglitazone decreased pulmonary artery smooth muscle cell proliferation. These intra-amniotic treatments did not show any negative effects in either CDH fetuses or control fetuses. Conclusion: IA injection of sildenafil and rosiglitazone late in gestation ameliorates the pulmonary hypertensive phenotype of CDH and may have utility in clinical translation. Level of Evidence: Not applicable.