Interplay Between FoxM1 and Dab2 Promotes Endothelial Cell Responses in Diabetic Wound Healing

Abstract

This study investigates the molecular underpinnings of endothelial dysfunction in diabetes, focusing on the roles of Disabled-2 (Dab2) and Forkhead Box M1 (FoxM1) in VEGFR2 signaling and endothelial cell function. Our research reveals critical insights into the downregulation of Dab2 and FoxM1 in endothelial cells (ECs) under hyperglycemic conditions that leads to impaired angiogenesis and delayed wound healing. These findings Substantiate our hypothesis that restoring Dab2 expression through targeted therapies could enhance angiogenesis and wound repair in diabetic environments. In vitro experiments involved treating primary murine brain ECs with high glucose concentrations, simulating hyperglycemic conditions in diabetes mellitus. Bulk RNA-sequencing analysis identified significant downregulation of Dab2, FoxM1, and genes involved in cell cycle progression, cell growth, survival, glycolysis, and oxidative phosphorylation. In vivo, ECs isolated from diabetic mice showed a marked decrease in Dab2 and FoxM1 compared to controls, validated by immunostaining and western blot analysis. Notably, FoxM1 was found to directly bind to the Dab2 promoter, regulating its expression and influencing VEGFR2 signaling. Dab2 deficiency led to enhanced lysosomal degradation of VEGFR2 in high-glucose-treated ECs, reducing VEGFR2 signaling. This was further supported by in vitro experiments showing decreased proliferation and angiogenic capability in Dab2-deficient brain ECs. Correspondingly, diabetic mice lacking Dab2 exhibited slower wound healing and reduced neovascularization. To explore therapeutic potential, we employed Dab2-mRNA encapsulated in lipid nanoparticles, significantly improving wound healing and angiogenesis in diabetic mice. This study provides substantial evidence of the crucial roles of Dab2 and FoxM1 in diabetic endothelial dysfunction and proposes targeted gene delivery systems as a promising treatment for diabetic vascular complications.