Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension

•Endothelin-1 is important in organogenesis and pulmonary arterial hypertension (PAH).•Endothelin-1 receptor antagonists (ERA) are teratogenic but beneficial for PAH.•Pregnancy in PAH is contraindicated and ERA treatment is strongly discouraged.•In PAH, the right ventricle (RV) enters a fetal gene program for adaptation.•ERA's may be harmful for RV contractility and adaptive hypertrophic remodeling. The Pregnancy Prevention Program (PPP) is in place to prevent drug-induced developmental malformations. Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERA's: ambrisentan, bosentan and macitentan), which are approved for the treatment of Pulmonary Arterial Hypertension (PAH). This review describes the effects of ERA's in PAH pathobiology and cardiopulmonary fetal development. While ERA's hamper pathological remodeling of the pulmonary vasculature and as such exert beneficial effects in PAH, they disturb fetal development of cardiopulmonary tissues. By blocking ET-1-mediated positive inotropic effects and myocardial fetal gene induction, ERA's may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the fetus and the adult PAH patient.