Mechanism of the epidermal growth factor receptor in promoting endothelial cell dysfunction in gestational diabetes mellitus.

Abstract

Background: Epidermal growth factor receptor (EGFR) is a transmembrane protein that is differentially expressed in gestational diabetes mellitus (GDM). Endothelial dysfunction is a hallmark of GDM and plays a key role in its pathogenesis. EGFR is associated with endothelial dysfunction in the context of various diseases. However, the exact mechanism by which EGFR causes endothelial dysfunction in GDM is unknown, particularly its regulation at the transcriptional and protein levels.

Aim: To explore the molecular mechanism by which EGFR influences endothelial cell dysfunction in GDM at the transcriptional and protein levels.

Methods: Quantitative real-time polymerase chain reaction was used to detect the expression of EGFR and H19. Western blotting was used to detect the expression of endothelial cell dysfunction markers. A cell counting kit 8 assay was used to assess cell viability, flow cytometry was used to assess apoptosis, scratch and Transwell assays were used to assess cell migration, and a tube formation assay was used to assess cell vascular formation. Hematoxylin-eosin staining was used to observe histopathological changes in the placentas of the mice.

Results: In this study, EGFR was upregulated in clinical samples, GDM animal models and GDM cell models, and the knockdown of EGFR could mitigate the effect of streptozotocin (STZ) and high glucose (HG); promoted the proliferation, migration and vascularization of human umbilical vein endothelial cells (HUVECs); inhibited cell apoptosis and the expression of endothelial cell dysfunction markers (vascular cell adhesion molecule-1, tumor necrosis factor-α, vascular endothelial growth factor-A, and intercellular cell adhesion molecule-1); and alleviated the process of GDM in vivo. Mechanistically, EIF4A3 binding to long noncoding RNA H19 increased the stability of EGFR messenger RNA, thereby promoting HG-induced HUVECs dysfunction or STZ-induced endothelial cell dysfunction in GDM mice. In addition, ERRFI1 also regulated the expression of EGFR, and ERRFI1 inhibited EGFR activity by binding to EGFR, thereby inhibiting HG-induced HUVECs dysfunction.

Conclusion: Our study revealed that EGFR can accelerate the development of GDM by promoting endothelial cell dysfunction.