Gestational High‐Altitude Hypoxia and Metabolomic Reprogramming in Pulmonary Arteries from Fetal Sheep

Abstract

Gestational high‐altitude hypoxia increases the risk of myriad diseases in human infants including pulmonary hypertension of the newborn. Fetal sheep lungs are susceptible to long‐term intrauterine hypoxia, with the lung structure and function exhibiting characteristics associated with the development of pulmonary hypertension. Previous studies showed thickening of the pulmonary arterial medial wall, dysregulation of arterial reactivity, and reduced right ventricular output in fetal lambs following exposure to high altitude long‐term hypoxia. To further explore the mechanisms associated with hypoxia‐induced aberrations in the fetal sheep lung, we examined the premise that metabolomic and proteomic changes are associated with phenotypic transformation caused by intrauterine hypoxia. To address this hypothesis, we performed metabolomic and proteomic analysis on pulmonary arteries isolated from near term fetal lambs that were exposed to intrauterine high‐altitude hypoxia (3801 m) for the latter 110+ days of pregnancy or those gestated near sea level. The data demonstrated gestational hypoxia caused a glycolytic shift, reduced fatty acid oxidation, and elevated pentose phosphate metabolism along with increased histone expression, illustrative of increases in nucleotide synthesis. Increased nucleotide synthesis in response to gestational hypoxia is suggestive of a shift towards a proliferative and synthetic phenotype, providing insight into the mechanisms related to gestational hypoxia‐mediated pulmonary remodeling and hypertension. These studies begin to shed light on the mechanistic underpinnings associated with the phenotypic transformations to the pulmonary vasculature that occur with intrauterine hypoxia.Support or Funding InformationSupported in part by NIH grants HD083132 (LZ), 1U24DK097154 (OF ) through a pilot project grant to SMW and HD098477 (SMW). Additional support was provided by USDA Intramural projects #2032‐51530‐022‐00D and #2032‐51530‐025‐00D (J.W.N.). The USDA is an equal opportunity provider, and employer.