Endometrial Receptivity In The Peri-implantation Endometrium Of High Ovarian Response And Recurrent Implantation Failure

AimIn in vitro fertilization-embryo transfer(IVF-ET),endometrial receptivity(ER)damage is considered to be the main cause of embryo implantation failure.There are many potential factors affecting ER,but studies have been limited to uterine glandular epithelial tissue,and little research has been focused on the extracellular matrix and blood vessels of the endometrium.This study investigated whether high estrogen and progesterone in patients with high ovarian response affect endometrial collagen synthesis and related gene expression during peri-implantation and explore whether there is a differential expression of angiogenesis-related factors in recurrent implantation failure(RIF)women with elevated uterine arterial impedance.MethodsWe compared the endometrial collagen content,the expression of matrix metalloproteinases 2 and 9(MMP2,9)and tissue inhibitors of metalloproteinases 1 and 3(TIMP1,3)in the stimulation cycle(SC)group and the natural cycle(NC)group women.Estrogen,progesterone and their corresponding receptor antagonists were added in a concentration gradient to detect the expression of MMP2,9 and TIMP1,3 at the RNA and protein levels in human endometrial stromal cell lines(HESCs).The serum level and endometrial expression of ANGPTL4 were compared between the RIF group with elevated uterine arterial impedance and the control group.The expression of ANGPTL4 and upstream peroxisome proliferator-activated receptor gamma(PPAR?)were measured between HESCs and nature cells.Different concentrations of rosiglitazone were added to observe the expression changes of ANGPTL4 and PPAR?.The effects of ANGPTL4 on proliferation,migration and angiogenesis of human umbilical vein endothelial cells(HUVECs)were observed by si RNA knockdown of ANGPTL4 and addition of rosiglitazone for cell proliferation assay,wound-healing assay and tube formation assay.ResultsThe modified Masson staining results showed that the collagen distribution was denser and the percentage of collagen density was higher in the stroma of the SC group than those in the NC group.MMP2 and MMP9 were detected significantly lower in the SC group than those in the NC group,while TIMP1 and TIMP3 were significantly higher.MMP2,9 expressions are increased by estrogen and MMP2 expression reduced by progesterone in dose-dependent manner through estrogen receptor(ESR)and progesterone receptor(PR).Correspondingly,TIMP1,3 expressions decreased by estrogen dose-dependently while progesterone played the opposite role.ANGPTL4 expression and secretion were decreased in endometrium and serum during peri-implantation period of RIF compared with control.PPAR? and ANGPTL4 expression were up-regulated upon decidualization of h ESCs.Rosiglitazone promoted the expression and secretion of ANGPTL4 in h ESCs and HUVECs via PPAR?.ANGPTL4 can promote proliferation,migration and angiogenesis of HUVECs.ConclusionsHigh ovarian response leads to elevated estrogen and progesterone in IVF-ET women,which stimulates the excessive synthesis of endometrial collagen,leading to impaired endometrial receptivity and affecting embryo implantation.The mechanisms may be related to high levels of P4 stimulate the decrease of MMP2 and the increase of TIMP1,3 through P4 receptor.Recurrent implantation failure women with elevated uterine arterial impedance had decreased expression and level of ANGPTL4 in endometrial tissue and serum in peri-implantation period.Rosiglitazone promotes angiogenesis by improving the expression of ANGPTL4 via PPAR?,which improves endometrial receptivity,thus benefits embryo implantation.