TY - JOUR
T1 - Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis
T2 - Role of endothelin-1
AU - Harris, Alex K.
AU - Hutchinson, Jim R.
AU - Sachidanandam, Kamakshi
AU - Johnson, Maribeth H.
AU - Dorrance, Anne M.
AU - Stepp, David W.
AU - Fagan, Susan C.
AU - Ergul, Adviye
PY - 2005/9
Y1 - 2005/9
N2 - The risk of cerebrovascular disease is four- to sixfold higher in patients with diabetes. Vascular remodeling, characterised by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetes-mediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic Goto-Kakisaki (GK) rats were administered an ETA receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ET A receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ETA receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodelling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ETA receptor antagonism may offer a novel therapeutic target.
AB - The risk of cerebrovascular disease is four- to sixfold higher in patients with diabetes. Vascular remodeling, characterised by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetes-mediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic Goto-Kakisaki (GK) rats were administered an ETA receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ET A receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ETA receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodelling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ETA receptor antagonism may offer a novel therapeutic target.
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U2 - 10.2337/diabetes.54.9.2638
DO - 10.2337/diabetes.54.9.2638
M3 - Article
C2 - 16123352
AN - SCOPUS:24144442641
SN - 0012-1797
VL - 54
SP - 2638
EP - 2644
JO - Diabetes
JF - Diabetes
IS - 9
ER -
