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Interplay Between FoxM1 and Dab2 Promotes Endothelial Cell Responses in Diabetic Wound Healing
Sudarshan Bhattacharjee1,2, Jianing Gao1,2, Yao Wei Lu1,2
1Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA.
Biorxiv : the Preprint Server for Biology
|September 10, 2024
Summary
Restoring Disabled-2 (Dab2) expression enhances blood vessel formation and wound healing in diabetes by targeting endothelial cells. This study highlights Dab2 and FoxM1 roles in diabetic complications and suggests targeted therapies for vascular repair.
Area of Science:
- Endocrinology and Metabolism
- Molecular Biology
- Vascular Biology
Background:
- Diabetes mellitus impairs wound healing, increasing amputation risk.
- Mechanisms of impaired vascular endothelial growth factor (VEGF)-dependent angiogenesis in diabetes are not fully understood.
- Endothelial dysfunction is a key factor in diabetic complications.
Purpose of the Study:
- To investigate the roles of Disabled-2 (Dab2) and Forkhead Box M1 (FoxM1) in diabetic endothelial dysfunction.
- To elucidate the impact of Dab2 and FoxM1 on VEGF receptor 2 (VEGFR2) signaling and endothelial cell (EC) function.
- To evaluate the therapeutic potential of restoring Dab2 expression for diabetic wound healing.
Main Methods:
- Bulk RNA-sequencing of primary mouse skin ECs under high glucose conditions.
- Assessment of angiogenesis in diabetic mice with genetic endothelial cell-specific deficiency of Dab2.
- In vivo and in vitro functional assays for angiogenesis and wound healing.
- Treatment with mRNA-containing lipid nanoparticles (LNPs) for Dab2 restoration.
- Investigation of FoxM1 binding to the Dab2 promoter and its effect on VEGFR2 signaling.
Main Results:
- Dab2 was significantly downregulated in high glucose-treated ECs.
- Endothelial cell-specific deficiency of Dab2 reduced angiogenesis in diabetic mice.
- Restoration of Dab2 expression via mRNA-LNPs improved angiogenesis and wound healing.
- FoxM1 was downregulated in high glucose conditions and directly regulated Dab2 expression.
- FoxM1 inhibition reduced Dab2 expression and VEGFR2 phosphorylation.
Conclusions:
- Dab2 and FoxM1 play critical roles in diabetic endothelial dysfunction.
- Restoring Dab2 expression is a promising therapeutic strategy for enhancing angiogenesis and wound repair in diabetes.
- Targeted delivery of Dab2 mRNA using LNPs effectively improves wound healing and angiogenesis in diabetic mice.
- This study establishes targeted delivery as a viable approach for treating diabetic vascular complications.
