Multi-Omics Integration and the Development of Gestational High Altitude Induced Pulmonary Arterial Hypertension.

High altitude (> 2500 meters) during pregnancy reduces oxygen delivery to the fetus (i.e., gestational hypoxia), causing abnormal fetal lung development. The pulmonary arteries become thicker and less functional, increasing the risk of pulmonary hypertension, which is a multiorgan disease that promotes right heart failure and under five-years mortality rate. Our previous work showed endoplasmic reticulum stress and metabolomic alterations in fetal sheep pulmonary arteries indicative of an unregulated inflammatory response after gestational hypoxia. To understand the relationships between inflammation, vascular remodeling, and pulmonary arterial hypertension development, we examined the omic links between the pulmonary arteries and plasma exosomes in fetal sheep exposed to high altitude (3801 meters) for the majority of the pregnancy (110+ days out of 138-141 days of pregnancy). Specifically, metabolomics and proteomic analyses from the pulmonary arteries and transcriptomic analysis of plasma exosomes were integrated from fetal sheep to understand the mechanisms driving this multiorgan disease. Sixteen miRNAs and 75 proteins were differentially expressed between normoxic and hypoxic samples. Gestational hypoxia resulted in significant changes in 90 metabolites in fetal pulmonary arteries. These results show exosomal microRNA are linked with pulmonary artery proteins and metabolites important to cell membrane composition which might explain their role in the facilitation of changes in vascular remodeling, inflammation, and cell signaling. Top canonical pathways noted in omics data integration were acute phase response signaling, atherosclerosis signaling, FXR/RXR activation, intrinsic prothrombin activation pathway, and LXR/RXR activation. This multi-omics study illustrates the intricacy of complex adaptations that occur in the fetal sheep lung in response to gestational hypoxia.