The role of Dab2 in regulating angiogenesis in diabetes

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. 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. Conversely, enforced expression of Dab2 in endothelium by nanotherapy reversed diabetic vascular complication. Conclusions: Our study indicates that VEGF-induced angiogenesis is inhibited in diabetic conditions and Dab2 loss weakens VEGF signaling and angiogenic responses. Enhancing Dab2 expression could be a therapeutic target for enhancing angiogenesis during wound healing in diabetes. Mechanisms regulating VEGF receptors in diabetic angiogenesis The major goal of this R01 is to decipher molecular mechanisms of VEGFR downregulation in diabetes. R01HL130845 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.