Ovarian hyperstimulation reduces vascular endothelial growth factor-A during uterine receptivity

The angiogenic factor vascular endothelial growth factor-A (VEGFA) plays a critical role during early pregnancy in many species including the rat, and any alterations in VEGFA levels can severely impact blastocyst implantation rates. The rat ovarian hyperstimulation (OH) model is useful in studying how the induction of superovulation affects VEGFA levels and endometrial receptivity to blastocyst implantation. The present study shows that the major isoform in the rat uterus, Vegf₁₈₈ , is reduced at the time of receptivity in OH compared to normal pregnancy, whereas there is no change in Vegf₁₆₄ and Vegf₁₂₀ messenger RNA (mRNA). The VEGFA receptor 2 (VEGFR2) protein levels are also reduced at the time of receptivity in OH. Our ovariectomy studies show that Vegf₁₆₄ , Vegf₁₈₈ , and Vegf₁₂₀ are significantly decreased by estrogen, and, to a lesser extent progesterone, when compared to control animals. Although no change in the percentage of endometrial blood vessels was seen across all stages of pregnancy, at the time of receptivity in OH pregnancies, blood vessels were typically larger compared to other stages. The altered progesterone–estrogen ratio seen in OH, taken together with our ovariectomy studies, explains the changes to Vegfa mRNA in OH at the time of receptivity. Since VEGFA is important during implantation, the changes to Vegfa and VEGFR2 levels in the endometrium may help explain the observed lower endometrial receptivity following OH. This study aimed to analyse how ovarian hyperstimulation alters the levels of vascular endothleial growth factor and its major receptor, VEGFR2 in the uterus in a rat model.