Dual endothelin receptor antagonism with bosentan reverses established vascular remodeling and dysfunctional angiogenesis in diabetic rats: Relevance to glycemic control

Abstract

AimsWe have shown that diabetes causes cerebrovascular remodeling in part by the activation of the endothelin (ET-1) system in a glucose-dependent manner. We also reported increased yet dysfunctional cerebral angiogenesis in diabetes. Here, we tested the hypothesis that dual ET-1 receptor antagonism or glycemic control can reverse already established diabetes-induced vascular remodeling and neovascularization. Main methods18-week non-obese type-2 diabetic Goto-Kakizaki (GK) were treated with vehicle, metformin (300mg/kg/day) or bosentan (100mg/kg/day) for 4weeks by oral gavage and compared to 10 and 18-weeks GK rats. Isolated middle cerebral artery (MCA) lumen diameter (LD), media thickness (MT), media:lumen (M:L) ratio, and cross-sectional area (CSA) were measured using pressurized arteriograph. Assessment of remodeling and angiogenesis in the brain parenchyma was achieved by three-dimensional reconstruction of fluorescently labeled images of the vasculature acquired by confocal microscopy, and measurement of neovascularization indices including vascular volume and surface area, branch density and tortuosity. Key findingsMCA remodeling (increased M:L ratio and CSA, but decreased LD) occurred by 18weeks and did not progress by 22weeks in diabetic GK rats. Metformin and bosentan partially corrected large artery remodeling. Both treatments significantly reduced all indices of neovascularization compared to untreated diabetic rats. SignificanceGlycemic control or ET-1 antagonism can partially reverse diabetes-induced cerebrovascular remodeling and neovascularization. These results strongly suggest that either approach offers a therapeutic benefit and combination treatments need to be tested.