Placental expression and methylation of angiogenic factors in assisted reproductive technology pregnancies from India

This study aims to examine the gene expression and DNA methylation patterns of angiogenic factors in the placentae of Indian women who underwent assisted reproductive technology (ART) procedures and their association with maternal one-carbon metabolites and birth outcome. Placental gene expression and DNA methylation of angiogenic factors (<i>VEGF</i>, <i>PlGF</i>, <i>FLT-1</i>, <i>KDR</i>) in Indian women who underwent ART procedures (<i>n</i> = 64) and women who conceived naturally (Non-ART) (<i>n</i> = 93) was investigated using RT-qPCR and Epitect Methyl-II PCR assay kits. Maternal plasma one-carbon metabolites were assessed by CMIA technology. Gene expression of <i>FLT-1</i> and <i>KDR</i> was higher (<i>p</i> &lt; 0.05) in the ART placentae. Placental global DNA methylation levels were higher (<i>p</i> &lt; 0.01) and DNA methylation levels of <i>VEGF</i> promoter were lower (<i>p</i> &lt; 0.05) in ART compared to non-ART women. Maternal plasma folate and vitamin B₁₂ levels were higher (<i>p</i> &lt; 0.01) in the ART group. Gene expression of <i>PlGF</i> was negatively associated with maternal plasma folate (<i>p</i> &lt; 0.05) whereas KDR was positively associated with maternal plasma homocysteine (<i>p</i> &lt; 0.05). Gene expression of <i>KDR</i> was positively associated with chest circumference of the baby (<i>p</i> &lt; 0.05). Hypomethylation of <i>VEGF</i> and increased expression of <i>FLT-1</i> and <i>KDR</i> was observed in the placentae of women who underwent ART procedure. Assisted reproductive technology (ART) procedures such as in vitro fertilization (IVF) and intrauterine insemination (IUI) are used as infertility treatments. In India, the rate of infertility is on the rise thereby increasing the demand for these treatments. ART procedures are undertaken during gametogenesis and early embryo development. These are important stages where epigenetic modifications like DNA methylation are established for normal fetal development. ART procedures overlap with these stages, potentially affecting gene activity which may influence the development of the placenta and fetus. Evidence suggests that ART techniques are associated with maldevelopment and dysfunction of the placenta that would affect the fetal growth and development. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF), fms-like tyrosine kinase (FLT-1) and kinase domain receptor (KDR) are growth factors that play an important role in the process of angiogenesis defined as formation of new blood vessels from existing blood vessels. This process is essential for the growth and development of the placenta as well as fetus. This study reports lower DNA methylation of <i>VEGF</i> and higher expression of <i>FLT-1</i> and <i>KDR</i> in the placentae of Indian women who underwent ART procedures. These changes within the placenta are likely to influence angiogenesis, placental, and fetal growth.