Background: Pulmonary hypertension of the newborn is a life-threatening disorder characterized by elevated pulmonary vascular resistance due to maladaptation of the pulmonary circulation after birth. The pathogenesis and mechanisms underlying pulmonary hypertension of the newborn remain unclear, hindering the development of effective treatment. We hypothesize that perinatal chronic hypoxia upregulates microRNA-210, which is essential for suppression of pulmonary arterial spontaneous transient outward currents (STOCs), resulting in pulmonary hypertension of the newborn.
Methods: We tested this hypothesis in a large animal model of pregnant sheep and newborn lambs exposed to chronic hypoxia by comparing loss- versus gain-of-function of microRNA-210.
Results: Chronic perinatal hypoxia increases pulmonary vascular resistance and pulmonary arterial pressure in newborn lambs. The effect was mainly mediated by hypoxia after birth in the newborn. Mechanistically, we showed a significant decrease in microRNA-210 in pulmonary arteries after birth, but newborn hypoxia abolished this birth-induced reduction. We found that microRNA-210 mimic suppressed STOCs in newborn pulmonary arteries, and knockdown of microRNA-210 by microRNA-210-LNA prevented the hypoxia-induced reduction of pulmonary arterial STOCs. In vivo loss-of-function and gain-of-function experiments reveal that microRNA-210 is essential in the hypoxia-induced suppression of pulmonary arterial STOCs, increased pulmonary vascular resistance, and pulmonary hypertension in newborn lambs. Mechanistically, microRNA-210 suppressed pulmonary arterial STOCs via downregulation of iron-sulfur cluster assembly enzyme and large-conductance Ca2+-activated K+ channels.
Conclusions: We provide explicit evidence that neonatal hypoxia increases microRNA-210 expression, which is essential for suppression of STOCs, resulting in pulmonary hypertension in newborn lambs. Our study reveals new insights into the mechanisms and clinically meaningful targets for treatment of pulmonary hypertension of the newborn.
Keywords: animals; hypoxia; iron; pregnancy; pulmonary artery.