Abstract 492: The Role Of Dab2 In Regulating Angiogenesis In Diabetic Conditions

Abstract

Background: Diabetes-related vascular complications underlie a number of life-threatening conditions including cardiovascular disease, stroke, and peripheral limb ulcerations, the latter of which can lead to severe infections and a multitude of serious medical issues. Vascular endothelial growth factor receptor 2 (VEGFR2) is a critical regulator of physiological and pathological angiogenesis. Therefore, VEGFR2 signaling should be tightly controlled to promote neovascularization when beneficial vascular regeneration is reduced, and to attenuate angiogenesis when adverse vascular growth is excessive. Activated VEGFR2 endocytosis through a unique endocytosis adaptor protein called Disabled 2 (Dab2) results in enhanced VEGF signaling. However, the mechanisms underlying how Dab2 controls diabetic angiogenesis and the therapeutic potential of manipulation of Dab2 levels in diabetes are yet to be discovered. Hypothesis: We hypothesized that Dab2 plays a critical role in promoting angiogenesis in diabetes by amplifying VEGF signaling. Methods and Results: Using endothelial cell-specific inducible Dab2 knockout mice (EC-iDab2KO), we showed that VEGF signaling in primary mouse brain endothelial cells from EC-iDab2KO mice was greatly reduced compared to WT cells, which is reflected by decreased VEGFR2, Akt, and ERK phosphorylation. RNA sequencing also revealed decreased expression of Dab2 in EC in diabetic condition. VEGF also decreased EC-iDab2KO endothelial cell migration and tube formation in vitro. We used wound healing and Matrigel plug assays in STZ-induced diabetic mice to show reduced angiogenesis delayed wound healing process compared to diabetic WT mice. Lack of Dab2 further diminished angiogenesis and delayed wound healing compared to WT mice. CRISPR-mediated mutation of Dab2 promoter and ChIP-PCR reveals that FoxM1 transcription factor regulates Dab2 expression in endothelial cells in diabetes. Conclusions: Our study indicates that VEGF-induced angiogenesis is inhibited in diabetic conditions and Dab2 loss weakens VEGF signaling and angiogenic responses. Stabilizing Dab2 could be a therapeutic target for enhancing angiogenesis during wound healing in diabetes.