IGFBP2 attenuates high glucose-induced endothelial dysfunction through PI3K/Akt/eNOS pathway activation

Endothelial dysfunction induced by hyperglycemia is a key event in diabetic vascular complications and is closely associated with impaired PI3K/Akt/eNOS signaling. Insulin-like growth factor-binding protein 2 (IGFBP2) has been implicated in metabolic regulation and cell survival, but its role in high glucose-induced endothelial injury remains unclear. In this study, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose (HG, 33 mM) for 24 hours and then treated with recombinant human IGFBP2 (rhIGFBP2, 200 ng/mL) for 60 minutes. HG reduced Akt/eNOS phosphorylation and nitric oxide (NO) production, increased the expression of ICAM-1, VCAM-1, and SELE, promoted IL-6, IL-8, and MCP-1 secretion, and enhanced apoptosis. rhIGFBP2 attenuated these HG-induced changes by restoring PI3K/Akt/eNOS signaling and NO production, reducing inflammatory activation, and decreasing apoptotic cell percentage. The effect of rhIGFBP2 on Akt/eNOS phosphorylation and NO production was broadly comparable to that of insulin under HG conditions. HG also increased p38 MAPK phosphorylation, whereas rhIGFBP2 showed only a non-significant decreasing trend. Importantly, PI3K inhibition with LY294002 abolished rhIGFBP2-induced Akt/eNOS activation, supporting the involvement of the PI3K/Akt/eNOS pathway. These findings suggest that IGFBP2 protects against HG-induced endothelial dysfunction mainly by activating PI3K/Akt/eNOS signaling and may represent a potential mediator of endothelial protection under diabetic conditions.