Diabetes-Induced Jagged 1 Overexpression in Endothelial Cells Causes Retinal Capillary Regression in a Murine Model of Diabetes Mellitus: Insights into Diabetic Retinopathy

BACKGROUND—Several mechanisms have been proposed to account for diabetes-induced microvasculopathy (DMV). While Notch signaling was reported to be affected by glucose metabolism in endothelial cells (EC) during developmental angiogenesis, it has not been investigated in vascular remodeling of adult capillaries in relation to diabetes mellitus (DM). METHODS—We induced DM in 8 week-old adult mice by intravenous administering of streptozotocin. After 6 weeks, we harvested organs including retina, heart and skeletal muscle and evaluated the capillaries with immunofluorescence and confocal microscopy. We modulated endothelial Notch signalling using chemical inhibitors in wild type mice or transgenic mice inducing conditional knockout of Jagged1 or Mib1. RESULTS—DMV was characterized by capillary remodeling, regression, and decreased density. Notch ligand Jagged1, but not Dll4, was markedly increased in EC of diabetic mice. Using endothelial specific-Jagged1 knockdown mice, we found that blocking Jagged1 prevented DMV even under diabetic conditions. Furthermore, using the inducible endothelium-specific Jagged1-knockdown mice, blocking Jagged1 even at 4 weeks after establishment of DMV could reverse it, leading to normalization of retinal vasculature. A search for downstream signals revealed that DM decreased the nuclear localization of Notch1 Intracellular Domain and reduced expressions of VE-cadherin and N-cadherin in EC. Chemical Notch inhibition phenocopied DMV in normal mice. CONCLUSIONS—Our findings indicate that diabetes induces Jagged1 overexpression and suppresses Notch signaling in endothelial cells, leading to DMV in adult mice. We conclude that dysregulated intercellular Notch signaling may be a novel mechanism of DMV.