Hyperinsulinemia restrains endometrial angiogenesis during decidualization in early pregnancy

Abstract

Previous research on the role of insulin has focused on metabolism. This study investigated the effect of insulin on angiogenesis in endometrial decidualization. High insulin-treated mouse model was constructed by subcutaneous injection of insulin. Venous blood glucose, serum insulin, P4, E2, FSH and LH levels in the pregnant mice were detected by ELISA. Decidual markers, angiogenesis factors and decidual vascular network were detected during decidualization in the pregnant mouse model and an artificially induced decidualization mouse model. Tube formation ability and angiogenesis factors expression were also detected in high insulin-treated HUVECS cells. To confirm whether autophagy participates in hyperinsulinemia-impaired decidual angiogenesis, autophagy was detected in vivo and in vitro. During decidualization, in the condition of high insulin, serum insulin and blood glucose were significantly higher, while ovarian steroid hormones were also disordered (P < 0.05), decidual markers BMP2 and PRL were significantly lower (P < 0.05). Uterine CD34 staining showed that the size of the vascular sinus was significantly smaller than that in control. Endometrial VEGFA was significantly decreased after treatment with high insulin in vivo and in vitro (P < 0.05), whereas ANG-1 and TIE2 expression was significantly increased (P < 0.05). In addition, aberrant expression of autophagy markers revealed that autophagy participates in endometrial angiogenesis during decidualization (P < 0.05). After treatment with the autophagy inhibitor 3-MA in HUVEC, the originally damaged cell tube formation ability and VEGFA expression were repaired. This study suggests that endometrial angiogenesis during decidualization was impaired by hyperinsulinemia in early pregnant mice.

Homeostatic Model Assessment for Insulin Resistance Is Associated With Late Miscarriage in Non-Dyslipidemic Women Undergoing Fresh IVF/ICSI Embryo Transfer

“…Except for this, altered maternal glucose and insulin metabolism would impact endometrial function on the transcriptomic and proteomic levels (40). Mice in early-stage pregnancy exposed to high insulin levels markedly compromised the decidualization process by attenuating endometrial vascularization and inhibiting endometrial stromal cells apoptosis (11,41). In the present study, we noted an increased prevalence of C type endometrium with the elevated trend of HOMA-IR level, suggesting a defective endometrial milieu among patients with IR.…”

An IGF1-expressing endometrial stromal cell population is associated with human decidualization

“…Interestingly, we observed a FOLR2 + IGF1 + M1 macrophage cluster with a M2-like phenotype was enriched in decidua, possibly contributing to accelerating decidualization. Additionally, endometrial angiogenesis is very important for decidualization [59,60]. Here, we found SC and immune cells (e.g., macrophage and NK cells) should be involved in angiogenesis by several cytokines, which needs to be further researched.…”

Exploitation of a shared genetic signature between obesity and endometrioid endometrial cancer

“…In colorectal cancer, ANG cleavage produces tRNA-derived stress-induced small RNAs (tiRNAs) that promote colorectal cancer metastasis ( 14 ). Meanwhile, elevated expression of ANG was found to affect endometrial angiogenesis in hyperinsulin-treated mice ( 15 ). Integrating previous reports and bioinformatics analysis, we hypothesized that ANG expression is associated with obesity and involved in EC progression by affecting tumor angiogenesis.…”