Interfering with Dusp2 alleviates high glucose-induced vascular endothelial cell dysfunction by promoting p38 MAPK pathway activation

Background: Hyperglycemia-induced vascular endothelial cell dysfunction is a major factor contributing to dia-betic lower extremity ischemia. We intend to investigate the role of Dusp2 in hyperglycemia-induced vascular endothelial cell dysfunction and related mechanisms.Methods: The human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG) as the cell model. Streptozotocin injection was performed to induce diabetes and femoral artery ligation was to induce hind limb ischemia in mice. The levels of Dusp2, p-p38 MAPK, E2F4, and p38 MAPK were evaluated by Western blot or quantitative real-time PCR. The laser Doppler perfusion imaging was conducted to measure blood flow re-covery. The cell counting kit-8, transwell, and tube formation assay were performed to evaluate cell prolifera-tion, migration, and angiogenesis, respectively. CD31 immunohistochemical staining was carried out to detect the capillary density of gastrocnemius. The dual-luciferase reporter gene assay and Chromatin immunoprecipi-tation assay were executed to explore the interaction between E2F4 and Dusp2.Results: Dusp2 was highly expressed in HG-induced HUVECs and diabetic lower extremity ischemia model mice. Interference with Dusp2 promoted cell proliferation, migration, and angiogenesis, as well as alleviated mouse diabetic hindlimb ischemia. Dusp2 knockdown up-regulated p-p38 MAPK levels. We verified the binding be-tween E2F4 and Dusp2. Overexpressing E2F4 suppressed Dusp2 levels and promoted cell proliferation, migra-tion, and angiogenesis, co-overexpression of Dusp2 reversed the results.Conclusions: Overexpressing E2F4 promotes endothelial cell proliferation, migration, and angiogenesis by inhibiting Dusp2 expression and activating p38 MAPK to alleviate vascular endothelial cell dysfunction under HG stimulation.

Automated summary

This study suggests that Dusp2 plays a crucial role in hyperglycemia-induced vascular endothelial cell dysfunction by inhibiting Dusp2 expression and activating p38 MAPK, leading to endothelial cell proliferation, migration, and angiogenesis.