Endothelial cell activation sustains estradiol-independent long-term sterile inflammation and promotes endometrial hyperplasia

In this study, we elucidate that increased expression of SHP2 in endothelial cells drives the inflammatory activation of endothelial cell through dephosphorylation of its substrate RIPK1 at Y380 site and thus further makes endothelial dysfunction by influencing the transcript factors AP-1 and its target gene IGF1 and inflammatory related genes. The inflammatory activated endothelial cells recruited and activated macrophages, which enhances the inflammatory activation of endothelial cells in a positive feedback manner. Increased growth factor IGF1 in tissue leads to abnormal gland epithelial cell proliferation. Therefore, all the results indicate the importance of tissue endothelial cells and long-term estradiol independent sterile tissue inflammation as regulators of the endometrium hyperplasia. Targeting tissue inflammation through SHP2 inhibition or other anti-inflammation strategies may be potential interventions of EH. Overall design: To investigate the role of SHP2 in regulating the gene expression in HUVEC after estradiol treatment, we treated HUVECs with estradiol or estradiol plus SHP2 inhibitor SHP099. We also knockdown SHP2 in HUVECs using virus to compare the same gene expression with that treated with SHP099 in the condition of estradiol.