Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis: Role of endothelin-1

Alex K. Harris, Jim R. Hutchinson, Kamakshi Sachidanandam, Maribeth H. Johnson, Anne M. Dorrance, David W. Stepp, Susan C. Fagan, Adviye Ergul

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2638-2644
Number of pages7
JournalDiabetes
Volume54
Issue number9
DOIs
StatePublished - Sep 1 2005

Fingerprint

Endothelin-1
Matrix Metalloproteinases
Type 2 Diabetes Mellitus
Collagen
Blood Vessels
Cerebrovascular Disorders
Matrix Metalloproteinase 1
Matrix Metalloproteinase 2
Middle Cerebral Artery
Vasoconstrictor Agents
Hypertrophy
Extracellular Matrix
Stroke
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis : Role of endothelin-1. / Harris, Alex K.; Hutchinson, Jim R.; Sachidanandam, Kamakshi; Johnson, Maribeth H.; Dorrance, Anne M.; Stepp, David W.; Fagan, Susan C.; Ergul, Adviye.

In: Diabetes, Vol. 54, No. 9, 01.09.2005, p. 2638-2644.

Research output: Contribution to journalArticle

Harris, Alex K. ; Hutchinson, Jim R. ; Sachidanandam, Kamakshi ; Johnson, Maribeth H. ; Dorrance, Anne M. ; Stepp, David W. ; Fagan, Susan C. ; Ergul, Adviye. / Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis : Role of endothelin-1. In: Diabetes. 2005 ; Vol. 54, No. 9. pp. 2638-2644.
@article{a2aa1320f297434ca008407a0dfcf185,
title = "Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis: Role of endothelin-1",
abstract = "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.",
author = "Harris, {Alex K.} and Hutchinson, {Jim R.} and Kamakshi Sachidanandam and Johnson, {Maribeth H.} and Dorrance, {Anne M.} and Stepp, {David W.} and Fagan, {Susan C.} and Adviye Ergul",
year = "2005",
month = "9",
day = "1",
doi = "10.2337/diabetes.54.9.2638",
language = "English (US)",
volume = "54",
pages = "2638--2644",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "9",

}

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 - 2005/9/1

Y1 - 2005/9/1

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.

UR - http://www.scopus.com/inward/record.url?scp=24144442641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24144442641&partnerID=8YFLogxK

U2 - 10.2337/diabetes.54.9.2638

DO - 10.2337/diabetes.54.9.2638

M3 - Article

C2 - 16123352

AN - SCOPUS:24144442641

VL - 54

SP - 2638

EP - 2644

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -