Long Term Hypoxia Reduces Levels of Oxylipins in Pulmonary Arteries and Venous Plasma of Fetal Sheep

Abstract

High‐altitude long term hypoxia (LTH) during gestation compromises the development and function of the pulmonary vasculature in the fetus and later in the newborn. This may manifest as fetal growth restriction as well as pulmonary hypertension following birth. While the physiological regulation regarding the effects of hypoxia are well‐known, the dysregulation that occurs at the cellular and molecular level is not yet completely understood. Exploring the effects of LTH using a metabolomic approach is advantageous in deciphering the etiology associated with the development of disease. LTH is well regarded for inducing oxidative stress and causing inflammation. A number of possible regulators associated with LTH stress include oxylipins and endocannabinoids, products of polyunsaturated fatty acid (PUFA) oxidation. We hypothesized that high‐altitude LTH would reduce the levels of oxylipins and endocannabinoids of pulmonary arteries and plasma in fetal sheep. To test the hypothesis, we obtained samples of plasma and pulmonary arteries from fetal normoxic and hypoxic sheep raised at 3,800 m. altitude starting on gestation day 30. Metabolite levels were quantified using ultra performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS). Chemical similarity enrichment analyses and visualization by complex pathway analyses was performed on the datasets. Our results support our hypothesis that select oxylipin concentrations were diminished in both venous plasma and pulmonary arteries. Omega‐3 PUFAs alpha linolenic acid (ALA) and eicosapentaenoic acid (EPA) were reduced in both plasma and pulmonary arteries. 15‐HEPE and 12‐HEPE, derivatives of EPA and important anti‐inflammatory mediators, were also significantly reduced by LTH in plasma and pulmonary arterial samples from fetal animals. We believe that our studies provide insight toward identifying key biomarkers of LTH stress that will afford effective and prompt diagnosis of the neonate's physiological response. This is important when it comes to treating diseases associated with gestational hypoxia, which affects numerous mothers and newborns worldwide.Support or Funding InformationThis material is based upon work supported by NIH grants P01HD083132 (LZ) and 1U24DK097154 through a pilot project grant to SMW. 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.