Year-end Sale % OFF 
Abstract
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 VEGF165 in luminal/glandular epithelial cells and stromal cells of the endometrium in normal menstrual cycles; however, less is known about the role and mechanism of VEGF165 in endometrial fibrosis. Herein, we report that VEGF165 is a key regulator in endometrial stromal cells to inhibit α-SMA and collagen 1 expression. Compared to human control subjects, patients with AS exhibited decreased VEGF165 expression in the endometrium along with increased fibrotic marker expression and collagen production. A fibrotic phenotype was shown in both mice with conditional VEGF reduction and VEGF165-deleted endometrial stromal cells. Exogenous VEGF165 could suppress TGFβ1-induced α-SMA and collagen 1 expression in human primary endometrial stromal cells. However, this beneficial effect was hindered when the expression of smad7 or Notch4 was inhibited or when Notch signaling was blocked, suggesting that smad7 and Notch4 are essential downstream molecules for VEGFA functioning. Overall, our results uncover a clinical targeting strategy for VEGF165 to inhibit pro-fibrotic differentiation of stromal cells by inducing DLL4/Notch4/smad7, which paves the way for AS treatment.
Highlights
Asherman’s syndrome (AS), characterized by severe endometrial damage due to curettage, endometritis, or other unknown etiologies[1], is a major cause of female secondary infertility[2]
The mRNA expression levels of α-SMA and collagen 1 significantly increased after the cells were stimulated with TGFβ1 (10 ng/mL), while they significantly decreased after the cells were subsequently treated with VEGF165 (10 ng/mL) (Fig. 4a)
(see figure on previous page) Fig. 6 Notch signaling activation is crucial for VEGF165-mediated anti-fibrotic differentiation of stromal cells. a Endometrial stromal cells were stimulated with 10 ng/mL TGFβ1 for 48 h
Summary
Asherman’s syndrome (AS), characterized by severe endometrial damage due to curettage, endometritis, or other unknown etiologies[1], is a major cause of female secondary infertility[2]. Vascular endothelial growth factor A (VEGFA), whose predominant isoform is VEGF165, is one of the factors that is significantly upregulated in both the epithelium and stroma during postmenstrual repair and the early proliferative phase in the endometrium. VEGFA is essential for rapid bursts of angiogenesis and regulates the reepithelization of the endometrium by participating in crosstalk between the epithelium and stroma[6,7]. Upregulation of VEGFA in the endometrium is usually an important indicator for evaluating therapeutic effects on endometrial injury[8,9]. It has been reported that impaired expression of VEGFA in hepatic, pulmonary or renal fibrosis further aggravates fibrotic
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
