Arterial enlargement in response to high flow requires early expression of matrix metalloproteinases to degrade extracellular matrix

Exp Mol Pathol. 2002 Oct;73(2):142-53. doi: 10.1006/exmp.2002.2457.


This study investigated the effects of high flow and shear stress on the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-2 (TIMP-2) during flow-induced arterial enlargement using a model of arteriovenous fistula (AVF) creation on the carotid artery with the corresponding jugular vein in Japanese white male rabbits. Flow increased 8-fold 7 days after AVF. Endothelial cells (EC) and smooth muscle cells (SMC) proliferated with internal elastic lamina (IEL) degradation in response to high flow and shear stress. Expression of MMP-2 mRNA peaked at 2 days (1700-fold) and maintained high level expression. MMP-9 mRNA gave a 10.8-fold increase within 2 days and decreased later. Their proteins were detected in EC and SMC. Membrane type-1-MMP (MT1-MMP) mRNA increased 121-fold at 3 days and maintained high expression. TGF-beta1 was increased after AVF. Two-peak up-regulation of Egr-1 mRNA was recognized at 1 and 5 days of AVF. These results suggest that high flow and shear stress can mediate EC and SMC to express MMP-2 and MMP-9, which degrade cell basement membranes and IEL to induce arterial enlargement. The disproportional increase in MT1-MMP and TIMP-2 might contribute to MMP-2 activation. Egr-1 and TGF-beta1 might play important roles in this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / anatomy & histology*
  • Arteries / enzymology*
  • Arteriovenous Fistula
  • Blood Flow Velocity
  • Carotid Arteries / anatomy & histology
  • Carotid Arteries / enzymology
  • Carotid Arteries / physiology
  • Carotid Arteries / surgery
  • Endothelium, Vascular / growth & development
  • Endothelium, Vascular / ultrastructure
  • Extracellular Matrix / metabolism*
  • Jugular Veins / physiology
  • Jugular Veins / surgery
  • Male
  • Matrix Metalloproteinase 2 / biosynthesis
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinases / biosynthesis*
  • Matrix Metalloproteinases / genetics
  • Muscle, Smooth / growth & development
  • Muscle, Smooth / ultrastructure
  • RNA, Messenger / metabolism
  • Rabbits
  • Regional Blood Flow
  • Stress, Mechanical
  • Time Factors
  • Tissue Inhibitor of Metalloproteinase-2 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Transforming Growth Factor beta / biosynthesis
  • Up-Regulation


  • RNA, Messenger
  • Transforming Growth Factor beta
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9