Objective: Diabetes promotes dysfunctional neovascularization and cerebrovascular remodeling in diabetes. We showed that glycemic control with metformin prevents and restores diabetes-mediated pathological remodeling and neovascularization of the cerebrovasculature. Our recent data suggest that linagliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor used for glycemic control, prevents vascular remodeling independent of glycemic control in diabetes. In this study, we test the hypothesis that linagliptin prevents dysfunctional neovascularization in a blood glucose independent manner in diabetes.
Methods: 24 week old diabetic Goto-Kakizaki (GK) (Hemoglobin A1C >6.5%) and nondiabetic Wistar rats were treated for 4 weeks with either vehicle chow or chow containing 166mg/kg linagliptin. At termination, FITC-dextran was injected to full and visualize the vasculature and brain sections were imaged by confocal microscopy for vascular density, tortuosity, vascular volume, and surface area measurements in 3 dimensional reconstruction of the cortex and striatum regions. Retinal acellular capillary formation was measured as another surrogate marker for pathological neovascularization in diabetes (n=3-4). Brain microvascular endothelial cells (BMVEC) isolated from control or diabetic rats were also treated with (100 nM) linagliptin and tested for angiogenic properties with cell migration and tube formation assays.
Results: Linagliptin reduced all indices of cerebral neovascularization compared with control rats (Table, n=3-5). In addition linagliptin significantly decreased retinal acellular capillaries and normalized the augmented angiogenic properties of diabetic BMVEC (p<0.05).
Conclusions: These results suggest that linagliptin offers therapeutic potential and effective in reversing established pathological neovascularization. Mechanisms underlying glucose independent effects of linagliptin remain to be determined.