Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR

Xue-Feng Xu,Ying Lv,Wei-Zhong Gu,Li-Zhong Du,Li-Yan Zhang,Li-Li Tang,Jia-Kai Wei

doi:10.1186/1465-9921-14-20

Abstract

BackgroundAccumulating evidence reveals that intrauterine growth retardation (IUGR) can cause varying degrees of pulmonary arterial hypertension (PAH) later in life. Moreover, epigenetics plays an important role in the fetal origin of adult disease. The goal of this study was to investigate the role of epigenetics in the development of PAH following IUGR.MethodsThe IUGR rats were established by maternal undernutrition during pregnancy. Pulmonary vascular endothelial cells (PVEC) were isolated from the rat lungs by magnetic-activated cell sorting (MACS). We investigated epigenetic regulation of the endothelin-1 (ET-1) gene in PVEC of 1-day and 6-week IUGR rats, and response of IUGR rats to hypoxia.ResultsThe maternal nutrient restriction increased the histone acetylation and hypoxia inducible factor-1α (HIF-1α) binding levels in the ET-1 gene promoter of PVEC in IUGR newborn rats, and continued up to 6 weeks after birth. These epigenetic changes could result in an IUGR rat being highly sensitive to hypoxia later in life, causing more significant PAH or pulmonary vascular remodeling.ConclusionsThese findings suggest that epigenetics is closely associated with the development of hypoxic PAH following IUGR, further providing a new insight for improved prevention and treatment of IUGR-related PAH.

Highlights

An adverse intrauterine environment, such as uteroplacental vascular insufficiency and maternal malnutrition, may impact the development of the fetus resulting in fetal growth restriction or intrauterine growth retardation (IUGR) [1,2]
The right ventricular systolic pressure (RVSP) of the IUGR hypoxia group was statistically significantly higher than that of the Control hypoxia group (P = 0.04), which indicates that IUGR rats were more sensitive to hypoxia than normal control rats
Similar to protein expression pattern, the ET-1 mRNA expression showed a similar trend (Figure 4C). These results indicate that the increased ET-1 level of IUGR hypoxia group rats might be responsible for the increased RVSP and pulmonary vascular remodeling changes

Summary

Introduction

An adverse intrauterine environment, such as uteroplacental vascular insufficiency and maternal malnutrition, may impact the development of the fetus resulting in fetal growth restriction or intrauterine growth retardation (IUGR) [1,2]. Their perinatal mortality is four to ten times higher than that of normally grown babies [1,3]. Epigenetic regulations in adult onset diseases following IUGR, including type 2 diabetes and hypertension, have been extensively investigated [5,15,16,17]. Accumulating evidence reveals that intrauterine growth retardation (IUGR) can cause varying degrees of pulmonary arterial hypertension (PAH) later in life.

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