Abstract W P357: Glycemic Control or Dual Endothelin Receptor Antagonism Reverses Diabetes-Mediated Dysfunctional Cerebral Neovascularization and Remodeling Patterns
OBJECTIVES: Diabetes targets micro and macrovascular endothelium leading to cardiovascular complications including stroke and cognitive impairment. We previously showed that 1) endothelin-1 (ET-1), the most potent vasoconstrictor with growth promoting properties, contributes to diabetes-mediated cerebrovascular dysfunction and remodeling, and 2) glycemic control started at the onset of diabetes prevents these vascular pathologies in part by decreasing the activation of the ET system. We recently demonstrated that diabetes causes dysfunctional cerebral neovascularization but whether these changes can be reversed remained unknown. The current study tested the hypothesis that glycemic control or dual ET receptor antagonism reverses established pathological neovascularization of the brain in diabetes.
METHODS: Diabetic male Goto-Kakizaki (GK) rats were administered either vehicle, metformin (300 mg/kg/day), or the dual ETA/ETB receptor antagonist bosentan (100 mg/kg/day) for 4 weeks (w) starting at 18 weeks of age after pathological neovascularization occurs. At termination (22 w), brain sections were imaged by confocal microscopy and vascular density, tortuosity, vascular volume, and surface area in the cortex and striatum regions were measured by 3-dimensional reconstruction of isolectin stained vasculature using Z-stacked images.
RESULTS: Metformin and bosentan treatment reduced all indices of neovascularization compared with untreated 22-w old GK rats (Table, n=3, *p<0.05). Blood glucose levels (mg/dL) in untreated, metformin-treated, and bosentan-treated rats were 242±25, 126±4, and 199±21, respectively. Mean arterial blood pressure was consistent across the groups.
CONCLUSION: These results suggest that glycemic control with metformin or use of dual ETA/ETB receptor antagonist is effective in reversing established pathological neovascularization and offers therapeutic potential.
Author Disclosures: J. Kaczmarek: None. M. Abdelsaid: None. S. Fagan: None. A. Ergul: None.
- © 2014 by American Heart Association, Inc.