Chronic Gestational Hypoxia Alters Plasma Exosomal miRNA Profile and Pulmonary Arterial Proteome and Metabolome in Fetal Lambs
Authors: Cardenas Anafernanda , Bhatnagar Aditi , Leslie Eric , Stuart Avery , Zacharias Johnathan , Petersen Garrett , Jones Breanna 
Published: May 2024

Antenatal chronic hypoxia negatively impacts fetal development and increases the risk of cardio-pulmonary dysfunction after birth, including newborn pulmonary hypertension. Previously, we showed that fetal and newborn sheep exposed to chronic hypoxia during gestation exhibit a variety of cardio-pulmonary defects that parallel those of human infants including pulmonary vascular remodeling, heart dysfunction, and pulmonary hypertension. To explore the mechanisms involved in hypoxia-mediated newborn pulmonary hypertension, we test the hypothesis that antenatal chronic hypoxia impairs pathways critical to pulmonary vascular development that are coupled to abnormalities in lung structure and function through dysregulation in cell growth and proliferation. To address this hypothesis, we employed an animal model of pregnant sheep exposed to high altitude hypoxia at the White Mountain Research Station, which has an altitude of 3801 meters. Hypoxic pregnant sheep were housed at altitude during gestation for ~110 days out of 138-141 days of pregnancy while normoxic counterparts were kept at 700 meters. Animals were transferred to Loma Linda at 355 meters and fetal lambs studied at ~140 days of gestation. Fetal plasma samples were collected for exosomal miRNA analysis and pulmonary arteries were collected for proteomic and metabolomic analysis. Ingenuity pathway analysis and other bioinformatic tools were used to interrogate regulatory mechanisms and pathways and the web of molecular interactions affected by hypoxia. Antenatal hypoxic stress caused up and down regulation of a limited number of plasma exosomal miRNAs, pulmonary arterial metabolites and proteins, with discrete interconnections between the various analytes and molecules. There were marked changes in upstream regulators and markers that point to increased oxidative stress and inflammatory response along with pronounced downregulation of matrix proteins and phenotypic markers of vascular smooth muscle cell differentiation. Pathway analyses indicate antenatal chronic hypoxia dysregulates growth and proliferation of vascular cells and impinges on cell migration. While these data require additional study and verification, they provide new insights in the understanding of mechanisms underlying the development of pulmonary hypertension in the newborn following antenatal hypoxia. This work was supported by the National Institutes of Health Grants NIH R01HL155295, R01HL149608, R03HD098477, P01HD083132, and U24DK097154. Additional support was provided by the Loma Linda University School of Medicine, A pilot Project through the West Coast Metabolomics Center, the University of Redlands Summer Research Program, and the Walter E. Macpherson Society. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.