Three-Dimensional Visualization of Mouse Endometrial Remodeling After Superovulation

Abstract

Uterine status determines pregnancy success. Although it is well known that superovulation operations can disrupt uterine function, our understanding of the morphological changes in the uterine endometrium at the three-dimensional (3D) level is limited. Here, combining the tissue clearing with 3D deep imaging, we reveal an increase in epithelial density and angiogenesis after ovarian stimulation, which is accompanied by a circulating surge in P4 levels. Using an ovariectomized mouse model, we further detected the separate regulatory effects of P4 and E2 on the uterine endometrium, with P4 promoting endothelial cell growth and E2 inducing epithelial proliferation. Additionally, we observed that the effects of E2 can be partially neutralized by P4, and vice versa. By analyzing the 3D uterine imaging, we discovered an interesting phenomenon in which the growing blood vessels closely surround the remodeling uterine epithelium, indicating a close relationship between angiogenesis and epithelial growth. These findings provide new insight into the uterine epithelial changes and angiogenesis at the 3D level, and explain a potential reason for endometrial changes due to the low implantation rate in patients undergoing clinic super-ovulation.

Knockout of Rlim Results in a Sex Ratio Shift toward Males but Superovulation Cannot Compensate for the Reduced Litter Size

“…It has been reported that superovulation in female mice leads to the expulsion of some low-quality oocytes [ 27 , 28 ] and produces an excessive number of embryos, which causes overload of the uterus [ 29 , 30 ] and impairment of fetal growth in utero [ 21 , 31 ]. The prenatal detrimental effects caused by superovulation in the mothers might increase the perinatal mortality of newborn mice.…”

Transcriptome profiling reveals superovulation with the gonadotropin-releasing hormone agonist trigger impaired embryo implantation in mice

“…Decreased VEGF expression in the ovaries was observed with the GnRHa trigger compared to the hCG trigger, which could explain the reduced ovarian hyperstimulation. Numerous research works have evaluated the ovarian, uterine, and fetal abnormalities caused by superovulation ( 18 – 20 ). Previous studies have shown that superovulation with the hCG trigger alters the expression of genes about tissue remodeling and placenta formation during implantation, resulting in abnormal placental and fetal growth ( 10 , 21 ).…”

“…Another study found that after the GnRHa trigger, the mouse uterus showed abnormal leukocyte distribution and higher inflammatory response ( 22 ). There are several studies showed that the use of HCG to trigger ovulation leads to impaired uterine receptivity ( 20 , 23 ). However, the effect of GnRHa-triggered protocols on embryo implantation has not been clarified, especially the ovarian and uterine changes in pre-implantation.…”