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


METHODS
18-week non-obese type-2 diabetic Goto-Kakizaki (GK) were treated with vehicle, metformin (300 mg/kg/day) or bosentan (100 mg/kg/day) for 4 weeks 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.


RESULTS
MCA remodeling (increased M:L ratio and CSA, but decreased LD) occurred by 18 weeks and did not progress by 22 weeks 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.


CONCLUSIONS
Glycemic 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.
Charlie Norwood Veterans Administration Medical Center, Augusta, GA, USA; Department of Physiology, Georgia Regents University, Augusta, GA, USA.
Mohammed
M
Abdelsaid
Department of Physiology, Georgia Regents University, Augusta, GA, USA.
Jessica
J
Kaczmarek
Department of Physiology, Georgia Regents University, Augusta, GA, USA.
Maha
M
Coucha
Charlie Norwood Veterans Administration Medical Center, Augusta, GA, USA; Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Department of Physiology, Georgia Regents University, Augusta, GA, USA. Electronic address: aergul@gru.edu.
Adviye
A
Ergul
D000818:Animals; D000077300:Bosentan; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D066253:Vascular Remodeling / Q000187:drug effects*
D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D000077300:Bosentan
Bosentan; Diabetes; Endothelin; Metformin; Neovascularization; Vascular remodeling