title: Arterial enlargement in response to high flow requires early expression of matrix metalloproteinases to degrade extracellular matrix.
abstract: 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.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5642, USA.
authors.forename: Eiketsu
authors.initials: E
authors.lastname: Sho
authors.forename: Mien
authors.initials: M
authors.lastname: Sho
authors.forename: Tej M
authors.initials: TM
authors.lastname: Singh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nanjo
authors.forename: Masayo
authors.initials: M
authors.lastname: Komatsu
authors.forename: Chengpei
authors.initials: C
authors.lastname: Xu
authors.forename: Hirotake
authors.initials: H
authors.lastname: Masuda
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Zarins
mesh_terms: D000818:Animals; D001158:Arteries / Q000033:anatomy & histology* / Q000201:enzymology*; D001164:Arteriovenous Fistula; D001783:Blood Flow Velocity; D002339:Carotid Arteries / Q000033:anatomy & histology / Q000201:enzymology / Q000502:physiology / Q000601:surgery; D004730:Endothelium, Vascular / Q000254:growth & development / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism*; D007601:Jugular Veins / Q000502:physiology / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D009130:Muscle, Smooth / Q000254:growth & development / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9