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

Abstract

Antenatal maternal hypoxia (AMH) can lead to intrauterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult, the latter of which 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 alterations in gene and protein expression of the pulmonary renin-angiotensin system, which may play an important role in pulmonary disorders in the offspring. In FVB/NJ mice, we studied messenger RNA (mRNA) and protein expression, as well as promoter DNA methylation and microRNA (miRNA) levels in response to 48 hours hypoxia (10.5% O(2)) 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 response to antenatal hypoxia, pulmonary protein levels of renin and ACE-2 also were increased significantly, whereas ACE-1 protein expression was reduced. In 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. In response to AMH, promoter methylation of ACE was unchanged. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. The possible implications of these changes for the regulation of pulmonary vascular contractility in later life remain to be explored.

Cardiovascular Transition to Extrauterine Life in Growth-Restricted Neonates: Relationship with Prenatal Doppler Findings

“…However, appropriate closure of this vessel with standard medical therapy suggests that permanent structural damage and altered responsiveness may only affect a small proportion of these babies [16]. Persistence of increased intrapulmonary blood flow resistance as a consequence of chronic intrauterine hypoxemia effects on the pulmonary vasculature is an alternative mechanism that is supported by the predominance of right to left shunting in animal experiments and observations in humans [17,18,19,20]. Absent UA EDV could predispose to pulmonary vascular remodeling through its association with chronic intrauterine hypoxemia, increased right-sided afterload and increased pulmonary artery blood flow resistance [21,22,23].…”

Epigenetic responses and the developmental origins of health and disease

“…Hypertension (Bogdarina et al 2007, Goyal et al 2009, type 2 diabetes mellitus (Williams et al 2008), cancer (Schmutte & Jones 1998), neurodegenerative disorders (Obeid et al 2009) to altered DNA methylation. In the antenatal proteindeprived mouse fetus, we observed hypomethylation (activation) of the promoter region of the angiotensin-I-converting enzyme (ACE) and increased ACE mRNA expression in the lung and brain (Goyal et al 2010(Goyal et al , 2011a. In hypertension ACE is an important enzyme target for pharmacological inhibitors (enalapril, lisinopril).…”

Decreased Cytokine and Chemokine mRNA Expression in Bronchoalveolar Lavage in Asymptomatic Smoking Subjects

“…Larger and smaller airways may react in different ways to various stimuli including cigarette smoke. The submucosa of the smaller airways of smokers has an increased number of neutrophils, activated and total eosinophils as well as a decreased CD4+/CD8+ T cell ratio compared with non-smokers and ex-smokers but no correlation with pulmonary function [9]. …”

“…Over 80% of COPD cases are caused by smoking [2, 3]. Cigarette smoke has acute and chronic effects on inflammation and responses in the airways [4,5,6,7,8,9,10,11]. …”