PAI-1 promotes human endometrial stromal decidualization via inhibiting VEGFR2/PI3K/AKT signaling pathway mediated F-actin reorganization

FASEB J. 2024 Dec 13;38(24):e70233. doi: 10.1096/fj.202401882R.

Abstract

Decidualization of endometrial stromal cells is a prerequisite for successful embryo implantation and early pregnancy. Decidualization dysregulation results in implantation failure. In our previous study, we reported that PAI-1 is abnormally downregulated in the endometrial tissue samples of patients with recurrent implantation failure. This study will explore the dynamic expression changes of PAI-1 in the endometrium during the menstrual cycle and its molecular mechanism affecting endometrial decidualization. Our findings indicated that the abundance of PAI-1 increased in the mid-secretory phase and attached a peak in the decidual phase in the endometrium of women with regular menstrual cycles. In human endometrial stromal cells (HESCs), PAI-1 knockdown attenuated endometrial decidualization by upregulating VEGFR2/PI3K/AKT signaling pathway and impaired the F-actin reorganization. Furthermore, axitinib (a VEGFR2 inhibitor) was used to inhibit the VEGFR2 protein activity and the results suggested that it eliminated the effects of PAI-1 on PI3K/AKT signaling pathways and F-actin remodeling. In addition, the interaction between PAI-1 and KNG1 was confirmed by coimmunoprecipitation assay in HESCs. Altogether, PAI-1-KNG1 may enhance the decidualization of endometrium by inhibiting VEGFR2/PI3K/AKT signaling pathway-mediated F-actin reorganization in healthy females.

Keywords: F‐actin; PAI‐1; PI3K/AKT signaling pathway; VEGFR2; decidualization.

MeSH terms

  • Actins* / metabolism
  • Adult
  • Cells, Cultured
  • Decidua* / cytology
  • Decidua* / metabolism
  • Endometrium* / cytology
  • Endometrium* / metabolism
  • Female
  • Humans
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Plasminogen Activator Inhibitor 1* / genetics
  • Plasminogen Activator Inhibitor 1* / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Signal Transduction*
  • Stromal Cells* / metabolism
  • Vascular Endothelial Growth Factor Receptor-2* / genetics
  • Vascular Endothelial Growth Factor Receptor-2* / metabolism

Substances

  • Proto-Oncogene Proteins c-akt
  • Vascular Endothelial Growth Factor Receptor-2
  • Phosphatidylinositol 3-Kinases
  • Actins
  • Plasminogen Activator Inhibitor 1
  • KDR protein, human