A comparison of mitochondrial respiratory function in adult and fetal sheep pulmonary arteries.

Abstract

Neonatal pulmonary hypertension (PH) occurs in approximately 6/1000 term infants. It results from insufficient vasodilation of the pulmonary arteries at birth, although the underlying etiology is not well understood. This increase in pulmonary arterial pressure can lead to severe systemic hypoxia due to redirection of blood flow away from the lungs via ductus arteriosus, resulting in systemic hypoxia. PH is more common in human fetuses exposed to chronic hypoxia during gestation, a phenomenon that is also demonstrated in our high‐altitude fetal sheep model.There is growing evidence that the mitochondria of pulmonary artery smooth muscle cells (PASMCs) play a key role in establishing vascular tone. Mitochondria are exposed to profound changes in oxygen and substrate availability in the transition from fetus to newborn. To gain a better understanding of the developmental changes in mitochondrial function in PASMCs, we tested the hypothesis that mitochondria from fetal vs adult PASMCs would display different substrate‐dependent rates of oxygen consumption and energy production.Lungs were surgically removed from adult non‐pregnant ewes or near‐term fetuses following greater than 100 days of residing at an altitude of over 3801 meters using protocols approved by the Loma Linda University IACUC. 4th–6th generation intrapulmonary pulmonary arteries were isolated, and denuded of endothelium. The metabolic activity of the arterial segments was analyzed in a Seahorse XFe 24 Analyzer that measures the oxygen consumption rate (OCR) with values being normalized to the arterial segment dry weight. These experiments were conducted in the presence of selective antagonists to enable determination of proton leak, non‐mitochondrial oxygen consumption, basal respiration, ATP‐linked respiration, maximal respiration, and spare capacity.Four adults and six fetuses were studied. Compared to adults, fetal PASMCs demonstrated a greater maximal respiratory capacity [813.99 +/− 73.20 (pmol/min) vs. 601.64 +/− 58.09 (pmol/min)] and spare‐capacity [593.28+/− 48.56 (pmol/min) vs. 353.74 +/− 40.39 (pmol/min)] for oxygen consumption while using carbohydrates and amino acids as substrates (p≤ 0.003, ANOVA). Other parameters of OCR were not different between fetuses and adults.These experiments provide initial evidence that there are maturational changes in mitochondrial function. Ongoing studies are evaluating the contribution of long‐term high altitude exposure to these differences in mitochondrial respiration and their importance to phenotypic and functional aberrations in lung function.Support or Funding Information(Supported in part by NIH grant HD083132 (ABB), HD098477 (SMW))