Elevated Expression of lncRNA MEG3 Induces Endothelial Dysfunction on HUVECs of IVF Born Offspring via Epigenetic Regulation.

Hong Chen,Fang Liu,Qiong Luo,Matthew Sagnelli,Yi-Chen Yu,Sai-Nan He,Yi-Min Zhu,Ying Jiang,Hong Zhu,Ye-Tao Xu

doi:10.3389/fcvm.2021.717729

Abstract

Cardiovascular dysfunction in children born after in vitro fertilization (IVF) has been of great concern, the potential molecular mechanisms for such long-term outcomes are still unknown. Here, we found that systolic blood pressure was a little higher in IVF born offspring at 2 years old compared to those born after being naturally conceived. Besides, the expression level of maternally expressed gene 3 (MEG3) was higher in human umbilical vein endothelial cells (HUVECs) from IVF offspring than that in spontaneously born offspring. Pearson correlation test showed that MEG3 relative expression is significantly related to the children's blood pressure (Coefficient = 0.429, P = 0.0262). Furthermore, we found decreased expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) along with elevated expression of endothelial-1(ET1) in HUVECs from IVF offspring, accompanied by lower secretion of nitrite, VEGF, and higher secretion of ET1 in the umbilical cord serum of IVF offspring. Correlation analysis showed MEG3 expression highly correlated with ET1 and Nitrate concentration. With pyrosequencing technology, we found that elevated expression of MEG3 was the result of hypomethylation of the MEG3 promoter. Therefore, our results provide a potential mechanism addressing the high-risk of hypertension in IVF offspring via MEG3 epigenetic regulation.

Highlights

Since the first in vitro fertilization (IVF) pregnancy was reported in 1978 [1], an estimated seven million pregnancies have been achieved worldwide by IVF
Children’s systolic blood pressure (SBE) at 2 years old, born by fresh in vitro fertilizationembryo transfer (IVF-ET) was slightly higher compared with those who were naturally conceived (84.1 ± 5.23 vs. 80.7 ± 4.85, P < 0.05), while there were no differences in the aspect of diastolic blood pressure and birth weight
By reviewing the baseline and perinatal characteristics of 903 babies (421 naturally conceived (NC) babies and 482 IVF babies) who were born in the past 4 years (2013–2016) in our hospital (Table 2), we found that there were no significant differences in S/D ratio, which are related to umbilical cord vessel function

Summary

Introduction

Since the first in vitro fertilization (IVF) pregnancy was reported in 1978 [1], an estimated seven million pregnancies have been achieved worldwide by IVF. An increasing number of studies have shown that IVF conceived fetuses are exposed to a high-estradiol environment in utero, which is closely correlated with increased risk of low birth weight (LBW) and small-for-gestationalage (SGA) [2, 3]. Disturbed intrauterine environments have been proven to be associated with rapid weight gain in early childhood, increased risk of high blood pressure in late childhood, a higher. Maternal undernutrition induced intrauterine growth retardation, which causes a significant decrease in the number of nephrons within 1 year of birth, could be an underlying mechanism in the early development of hypertension [7, 8]. The question as to how an intrauterine high-estradiol environment increases the risk of hypertension in IVF offspring later in life remains contentious [4, 9, 10]

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Results

Conclusion