The Effect Of Reduced Endometrial Vascular Endothelial Growth Factor On Endometrial Fibrosis In Patients With Intrauterine Adhesions And Its Mechanism

Background:Endometrial fibrosis is the main pathological feature of Asherman's syndrome(AS)which is the leading cause of uterine infertility.Much is known about the expression of VEGF1 65 in luminal/glandular epithelial cells and the stromal cells of endometrium in normal menstrual cycles,especially that there is lower expression in endometrial fibrosis.However,less is known about the role and mechanism of VEGF165 in endometrial fibrosis.Methods:This prospective study included endometrial samples from 100 women aged 18-40 years,recruited between January 2018 and December 2018,half with Asherman 's syndrome and half with regular menstrual cycles.All women had no signs of visible endometrial lesion under hysteroscopy.The expression of VEGF165 and fibrotic markers(collagen 1 and ?-SMA)were detected in endometrial samples from human and double transgenic mice VEGFtetO/tetO)/?-actin-tetR-Krab(?AKlg/wt)using quantitative real-time PCR(qRT-PCR),western blot,immunohistochemistry or immunofluorescence.Masson trichrome staining was also evaluated.The changes of fibrotic markers in stromal cells after undergoing VEGF165,smad7,Notch 1 or 4 knockdown or the related signaling inhibition were detected by qPCR,western blot or immunotluorescence.Results:Compared to the control individuals,VEGF165 expression in endometrium of AS was decreased,along with the increased expression of fibrotic markers(collagen 1 and ?-SMA).The fibrosis phenotype was shown in both VEGF165-repressed mice and VEGF165-deleted stromal cells.On the contrary,VEGF165 inhibited the increased fibrotic gene expressions in stromal cells induced by TGF?1.After stromal cells undergoing VEGF165,smad7,Notch 1 or 4 knockdown or the related signaling inhibition,the function of anti-fibrosis for VEGF165 would be significantly impaired.The anti-fibrosis function of VEGF165 is activated through inducing DLL4/Notch4/smad7 signaling.Conclusion:VEGF1 65 prevents endometrial fibrosis through promoting smad7 expression via activation of DLL4/Notch4 pathway to attenuate the transdifferentiation of endometrial stromal cells into myofibroblasts.The identification of VEGF165 as an inhibitor of fibrosis,opens the way for a growth factor and its dependent pathways to become a new prognostic and therapeutic target in patients with AS.