Antenatal Maternal Hypoxic Stress: Epigenetic Adaptations in Fetal Lung Renin‐Angiotensin System

Abstract

Antenatal maternal hypoxia (AMH) can lead to intra‐uterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult. This may be a consequence of alterations in the local pulmonary renin‐angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with fetal programming of the pulmonary renin‐angiotensin system. In FVB/NJ mice, we studied mRNA and protein expression, as well as promoter DNA methylation and miRNA levels in response to 48 hours hypoxia (10.5% O2) at 15.5 day post coitum (DPC). In response to AMH, the pulmonary mRNA levels of angiotensin converting enzyme (ACE) 1.2, ACE‐2 and angiotensin II type 1b (AT‐1b) receptors were increased significantly, as compared to controls (N=4). In hypoxia fetal lungs, protein levels of renin and ACE‐2 also were increased significantly, whereas ACE‐1 protein expression was reduced. In hypoxic fetal lungs, we also observed reduced expression of the miRNAs: mmu‐mir −199b, −27b, −200b, and −468 that putatively increase the translation of renin, ACE‐1, ACE‐2, and AT‐1 receptors, respectively. Promoter methylation of ACE did not change with AMH. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. This may have significant implications for the regulation of pulmonary vascular contractility in the lung.

Programming of Vascular Dysfunction by Maternal Stress: Immune System Implications

“…Considering that undernutrition imposes IUGR and a hypoxic environment to the fetus, the absence of oxygen may regulate a variety of oxygen-regulated genes, via HIFs ( Adams et al, 2009 ). miRNAs related to renin–angiotensin system components are affected by maternal hypoxia, and this genetic reprogramming may be involved in the development of pulmonary hypertension in adult offspring ( Goyal et al, 2011 ).…”