Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis: role of endothelin-1.
The risk of cerebrovascular disease is four- to sixfold higher in patients with diabetes. Vascular remodeling, characterized 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-Kakizaki (GK) rats were administered an ET(A) 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 ET(A) receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodeling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ET(A) receptor antagonism may offer a novel therapeutic target.
Harris
Alex K
AK
Medical College of Georgia, Clinical Pharmacy CJ-1020, Augusta, GA 30912, USA.
Hutchinson
Jim R
JR
Sachidanandam
Kamakshi
K
Johnson
Maribeth H
MH
Dorrance
Anne M
AM
Stepp
David W
DW
Fagan
Susan C
SC
Ergul
Adviye
A
D000818:Animals; D000077868:Atrasentan; D001786:Blood Glucose / Q000378:metabolism; D002536:Cerebral Arteries / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D013687:Telencephalon / Q000098:blood supply* / Q000502:physiology
D001786:Blood Glucose; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D003094:Collagen; D020782:Matrix Metalloproteinases; D000077868:Atrasentan