Chronic hypoxia in utero increases PAF receptor expression in lung vessels of fetal lambs

Abstract

The fetus is chronically in low oxygen environment that maintains a desirable high pulmonary vascular resistance (PVR) such that only 8–10% of total cardiac output passes through fetal lungs. With oxygenation, PVR falls dramatically, lung blood flow increases to accommodate the total cardiac output. Chronic hypoxia in utero leads to increase in vessel wall thickness and media wall area in pulmonary arteries of fetal lambs. Platelet activating factor (PAF) is an endogenous lipid molecule with different physiological and pathological properties. In ovine fetal pulmonary VSMC, hypoxia increases PAF receptor (PAFR) density and PAFR binding, indicating that high PAF level and its activities in fetal lungs are, in part, responsible for maintaining the desirable high fetal PVR in utero, but which postnatally manifest as persistent pulmonary hypertension of the newborn (PPHN). In spite of the tremendous advances in therapy of newborn respiratory diseases, PPHN still accounts for about 10–20% of neonatal mortalities. The magnitude and tissue distribution of PAFR expression in pulmonary vasculature of fetal lambs, in vivo, has not been examined. We hypothesized that chronic hypoxia in utero leads to over‐expression of PAFR and PAFR binding in fetal pulmonary vasculature that maintain high fetal PVR in utero. We obtained two groups of term pregnant ewes. One group was raised under low oxygen saturation (high altitude hypoxia, HAH). The other group was raised at sea level (normoxia). Fetuses were exteriorized from anesthetized ewes. Fetal lungs were harvested and sectioned for immunohistochemical staining and analytical microscopy of PAFR protein expression. Lung tissues and pulmonary vessel smooth muscle cells (SMC) were prepared and assayed for PAFR binding. We found that PAFR was expressed in the pulmonary vascular tissues of both groups of fetal lambs. Comparatively, PAFR protein fluorescence was greater in the HAH lung tissues in the internal elastin, endothelium, the smooth muscle layer and the adventitia. Baseline PAFR binding to vessel SMC of the HAH lambs was also greater. These data show that the greater PAFR expression in fetal hypoxic lung environment is in part, responsible for the high PVR of the fetal pulmonary circulation.