Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jun 15, 2025; 16(6): 105173
Published online Jun 15, 2025. doi: 10.4239/wjd.v16.i6.105173
Mechanism of the epidermal growth factor receptor in promoting endothelial cell dysfunction in gestational diabetes mellitus
Dan Tang, Cheng-Fen Wang, Jue Wang, Xiao-Tao Jing, Jing Ma
Dan Tang, Department of Obstetrics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
Cheng-Fen Wang, Jing Ma, Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
Jue Wang, Xiao-Tao Jing, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
Author contributions: Tang D contributed to conceptualization, investigation, project administration, validation, visualization, and writing-original draft; Jing XT contributed to data curation, methodology, and software; Wang CF and Wang J contributed to formal analysis and methodology; Ma J contributed to funding acquisition, resources, supervision, and writing- review and editing; All authors have read and approved the final manuscript.
Supported by the Youth Talent Program of Yunnan “Ten-thousand Talents Program”, No. YNWR-QNBJ-2018-169; and the Science Project of Yunnan Science and Technology Department, No. 202201AY070001-068.
Institutional review board statement: This study was officially approved by the Medical Ethics Committee of the First Affiliated Hospital of Kunming Medical University [approval No. (2021) L Review No. 36], and all patients participating in the study signed an informed consent form.
Institutional animal care and use committee statement: All animal experiment protocols were approved by the Animal Experiment Ethics Review Committee of Kunming Medical University (No. kmmu20220763). All methods were performed in accordance with the relevant guidelines and regulations and in accordance with the ARRIVE guidelines.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jing Ma, MD, Doctor, Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Kunming 650032, Yunnan Province, China. majing_dr@163.com
Received: January 15, 2025
Revised: March 29, 2025
Accepted: May 8, 2025
Published online: June 15, 2025
Processing time: 150 Days and 4.7 Hours
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.

Keywords: Gestational diabetes mellitus; Endothelial cell dysfunction; Epidermal growth factor receptor; EIF4A3; Long noncoding RNA H19; ERBB receptor feedback inhibitor 1

Core Tip: This study reveals that epidermal growth factor receptor (EGFR) drives endothelial cell dysfunction in gestational diabetes mellitus (GDM). EGFR upregulation in GDM models exacerbates dysfunction, while its knockdown enhances the proliferation, migration, and vascularization of human umbilical vein endothelial cells, and reduces the occurrence of apoptosis and the expression of dysfunction markers. Mechanistically, EIF4A3 stabilizes EGFR messenger RNA via long non-coding RNA H19, and ERRFI1 inhibits EGFR activity. EGFR emerges as a key therapeutic target for GDM.