Abstract
Gestational Hypoxia is a common prenatal stress caused by high altitude living, smoking, and other prenatal disorders. Such hypoxic insult can cause abnormalities in lung development that result in pulmonary hypertension in the newborn. Hypoxia is known to cause oxidative stress and accentuate glycolysis in adult tissues, effects which are intertwined with the development of various diseases. However, the adaptive responses of metabolism to long term hypoxia (LTH) in the fetal pulmonary vasculature is not nearly as well understood. The current work tests the hypothesis that following gestational LTH there is reduced antioxidant capacity and increased cellular glycolysis in neonatal sheep. For this study, normoxic pregnant and non‐pregnant sheep were obtained from Nebeker Ranch in Lancaster, CA (~700 meters) and were either sent to Loma Linda for study or to the White Mountain Research Station at an altitude of 3800 meters to induce LTH. After 110+ days at high altitude, animals were transported to Loma Linda University for the study. Pulmonary arteries of adult, 2‐week‐old newborn, and near‐term fetal sheep were isolated and frozen for analysis of primary metabolites. Metabolite levels were analyzed using Gas Chromatograph Time of Flight mass spectrometry (GC‐TOF MS) and visualized using enrichment and pathway analyses. LTH decreased the concentration of the antioxidant glutathione (GSH) and increased lactic acid, a byproduct of glycolysis, in adult and fetus. In the newborn LTH also decreased citric acid, a key intermediate in the Krebs cycle. These data indicate that the mother does not protect the pulmonary vasculature of the fetus from long term hypoxic stress due to gestation at high altitude. Thus, the fetus appears to be vulnerable even at modest altitudes to metabolic shifts and oxidative stress. Effects of these metabolic changes may persist after birth and contribute to the development of disease in the neonate or later in life.Support or Funding InformationThis material is based upon work supported by NIH grants P01HD083132 (LZ) and 1U24DK097154 through a pilot project grant to SMW as well as P20MD006988. IK was an Undergraduate Summer Research Fellow while RA was an Apprenticeship Bridge to College Scholar through the Center for Health Disparities and Molecular Mechanisms at Loma Linda University. VL is a recipient of the American Physiological Society's Short‐Term Research Education Program to Increase Diversity in Health‐Related Research (STRIDE) Fellowship funded by the APS and a grant from the National Heart, Lung and Blood Institute R25HL115473.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Published Version
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