Methylation-reprogrammed AGTR1 results in increased vasoconstriction by angiotensin II in human umbilical cord vessel following in vitro fertilization-embryo transfer

Zhang, Mengshu; Lu, Likui; Zhang, Yingying; Li, Xiang; Fan, Xiaoning; Chen, Xueyi; Tang, Jiaqi; Han, Bing; Li, Min; Tao, Jianying; Gao, Qinqin; Xu, Zhice; Sun, Miao

doi:10.1016/j.lfs.2019.116792

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…It has been reported to increase fasting blood glucose levels [8], blood pressure [8,9], adiposity, triglyceride levels [10], and vascular dysfunction [9,11,12] in IVF children. In our recent studies, we found that umbilical veins of IVF-ET offspring showed abnormal sensitivity to acetylcholine (ACh) or angiotensin II (AII)-mediated contraction, which could be caused by hypo/hypermethylation of the speci c receptors [13,14]. Our ndings strongly supported the idea that IVF-ET could directly lead to changes in fetal vessel functions, which might result in cardiovascular disorders in the long term.…”

supporting

confidence: 73%

GDF15 negatively regulates RGS16 involving in abnormal lipid metabolism in IVF-ET male mice offspring

Liu

Zhu²,

Zhu

et al. 2022

Preprint

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Background In vitro fertilization and embryo transfer (IVF-ET) is now widely used as a routine assisted reproductive technology (ART) procedure, and the long-term health outcomes of IVF-ET offspring are of great concern. A growing body of research suggests that children conceived through IVF-ET may be at increased risk for metabolic syndrome, type 2 diabetes, and cardiovascular disease. Methods An IVF-ET mouse model was established. Body weights and the principal organs were weighed, and organ/body weight indexes were calculated. The glucose metabolism levels were assessed by glucose tolerance test (GTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). The quantitative real-time PCR (RT-qPCR) technique was performed to determine the gene expression profiling in livers; HepG2 cells were transfected with either interfering RNA or overexpression plasmids to investigate the gene functions. mRNA and protein expression of relevant genes was verified by RT-qPCR and protein immunoblotting. Results Compared with the natural mating control group, male IVF-ET offspring showed: Higher body, liver, and epididymal white adipose tissue (eWAT) weight; Disrupted glucolipid metabolism with abnormal GTT, ITT, and PTT; Significantly decreased GDF15 expression along with increased expression of RGS16. Furthermore, phosphorylation of ERK1/2 and AKT were significantly reduced in the IVF-ET group. In vitro HepG2 cell experiment showed that knockdown of GDF15 caused an abnormal increase in RGS16 expression and decreased phosphorylation of ERK1/2 and AKT, accompanied by increased lipid deposition; In contrast, overexpression of GDF15 reduced expression of RGS16. Simultaneous knockdown of both GDF15 and RGS16 reversed lipid deposition in HepG2 cells. Conclusion Down-regulation of GDF15 expression in liver tissues of IVF-ET male offspring results in elevated expression of RGS16, which causes the weakening of the downstream ERK1/2 and AKT phosphorylation pathways, leading to increased activity lipid deposition and abnormal lipid metabolism in the liver of IVF-ET male offspring. It is suggested that GDF15-RGS16-p-ERK1/2/p-AKT pathway plays a crucial role in liver lipid deposition in IVF-ET male offspring and could be a potential therapeutic target.

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supporting

confidence: 73%

GDF15 negatively regulates RGS16 involving in abnormal lipid metabolism in IVF-ET male mice offspring

Liu

Zhu²,

Zhu

et al. 2022

Preprint

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“…However, three of them did not perform an adjusted analysis by paternal age [ 33 , 42 , 44 ]. On the other hand, with regard to maternal age, 14 of the 50 included studies did not report the maternal age and, therefore, did not consider it in the adjusted analysis [ 25 , 34 , 36 , 48 , 50 , 54 , 55 , 60 , 62 , 63 , 65 , 69 , 72 , 73 ]. However, in four other studies, although reported, the analysis would not appear to be corrected by parental age [ 44 , 46 , 66 , 67 ].…”

Section: Resultsmentioning

confidence: 99%

“…In turn, this altered methylation pattern could be due to reduced expression of the DNA methyltransferase 3a ( DNMT3a ) gene, which is responsible for de novo DNA methylation. All of this makes the umbilical veins more sensitive to the effects of angiotensin II, since AGTR1 is the main mediator of vasoconstriction [ 73 ]. In addition, ART may be associated with reduced methylation of the promoter of the MEG3 gene.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation in Offspring Conceived after Assisted Reproductive Techniques: A Systematic Review and Meta-Analysis

Cannarella

Crafa

Mongioì

et al. 2022

JCM

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In the last 40 years, assisted reproductive techniques (ARTs) have emerged as potentially resolving procedures for couple infertility. This study aims to evaluate whether ART is associated with epigenetic dysregulation in the offspring. Methods. To accomplish this, we collected all available data on methylation patterns in offspring conceived after ART and in spontaneously conceived (SC) offspring. Results. We extracted 949 records. Of these, 50 were considered eligible; 12 were included in the quantitative synthesis. Methylation levels of H19 CCCTC-binding factor 3 (CTCF3) were significantly lower in the ART group compared to controls (SMD −0.81 (−1.53; −0.09), I2 = 89%, p = 0.03). In contrast, H19 CCCTC-binding factor 6 (CTCF6), Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1OT1), Paternally-expressed gene 3 (PEG3), and Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) were not differently methylated in ART vs. SC offspring. Conclusion: The methylation pattern of the offspring conceived after ART may be different compared to spontaneous conception. Due to the lack of studies and the heterogeneity of the data, further prospective and well-sized population studies are needed to evaluate the impact of ART on the epigenome of the offspring.

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“…There were no differences in the gene and protein expression levels of AGT, ACE1 and AT2R in liver tissues, while AT1R was upregulated in liver tissues of IVF offspring. Previous studies have found that the increased contraction of umbilical cord blood vessels by Ang II in human IVF offspring is due to the increased protein expression and transcription level of AT1R, which is caused by the decreased methylation level of AT1R due to the decreased expression of the methylase DNMT3A [37] . In research on blood pressure regulation and vascular function of IVF offspring, unbalanced expression of AT1R and AT2R receptors was found in mice, resulting in an enhanced vascular contraction response to AngII [38] .…”

Section: Discussionmentioning

confidence: 97%

Altered local RAS in the liver increased the risk of NAFLD in male mouse offspring produced by in vitro fertilization

Wei

Shi

et al. 2023

Preprint

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Background: Assisted reproductive technology (ART) is associated with an increased risk of adverse metabolic health in offspring, and these findings have been demonstrated in animal models without parental infertility issues. However, it is unclear what changes lead to abnormal metabolism. The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. Thus, we focused on the local RAS of the liver, which is the central organ for glucose and lipid metabolism in offspring conceived by in vitro fertilization (IVF), and studied the role of local liver RAS in metabolic diseases. Methods: Male C57BL/6 mouse offspring obtained by natural pregnancy and IVF were fed a standard chow diet or a high-fat diet (HFD) from 4 weeks of age through 16 weeks of age. We assessed glucose and lipid metabolism, hepatic histopathology, and the gene and protein expression of key RAS components. In addition, the blocker losartan was used from 4 weeks of age through 16 weeks of age to investigate the regulatory mechanisms of abnormal local RAS on metabolic activity in the IVF offspring liver. Results: The growth trajectories of IVF offspring body and liver weights were different from those of naturally pregnant offspring. Impaired glucose tolerance (IGT) and insulin resistance (IR) occurred in IVF-conceived male offspring. After continuous HFD feeding, male offspring in the IVF group underwent earlier and more severe IR. Furthermore, there was a trend of lipid accumulation in the livers of chow-fed IVF offspring. Hepatic steatosis was also more serious in the IVF offspring after HFD treatment. Type 1 receptor (AT1R), which is the primary receptor mediating the action of angiotensin (Ang) II, has been confirmed to be upregulated in IVF offspring livers. Losartan reduced or even eliminated most of the significant differences between the IVF and NC groups after HFD consumption. Conclusions: The upregulation of AT1R expression in the liver increased the activity of the local RAS, resulting in abnormal glucose and lipid metabolism and lipid accumulation in the liver, significantly increasing the risk of nonalcoholic fatty liver disease (NAFLD) in IVF offspring.

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Methylation-reprogrammed AGTR1 results in increased vasoconstriction by angiotensin II in human umbilical cord vessel following in vitro fertilization-embryo transfer

Cited by 9 publications

References 41 publications

GDF15 negatively regulates RGS16 involving in abnormal lipid metabolism in IVF-ET male mice offspring

GDF15 negatively regulates RGS16 involving in abnormal lipid metabolism in IVF-ET male mice offspring

DNA Methylation in Offspring Conceived after Assisted Reproductive Techniques: A Systematic Review and Meta-Analysis

Altered local RAS in the liver increased the risk of NAFLD in male mouse offspring produced by in vitro fertilization

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