title: Pressure distention compared with pharmacologic relaxation in vein grafting upregulates matrix metalloproteinase-2 and -9.
abstract: OBJECTIVE
  Autogenous vein bypasses are a common and effective method to treat occlusive disease. During surgical preparation, veins are routinely pressure distended to overcome vasospasm and twists. Distention, however, is believed to promote vascular remodeling and contribute to decreased graft patency. Pharmacologic vasorelaxation with a combination of effective vasodilators has been suggested as an alternative to pressure distention. The extracellular matrix (ECM)-degrading matrix metalloproteinases (MMPs) have been implicated in vascular remodeling and neointima formation. The purpose of the present study was to compare the effects of pressure distention with pharmacologic vasorelaxation on graft remodeling and regulation of MMP-2 and MMP-9 in porcine vein grafts.
  
  
  METHODS
  Carotid artery bypass utilizing internal jugular veins was performed in eight female white pigs. Jugular veins were randomized to receive pressure distention (300 mm Hg for 2 minutes) or a combination of vasodilators (the alpha-adrenergic antagonist phenoxybenzamine, 10 micromol/L; the Rho-kinase inhibitor HA-1077 [fasudil], 50 micromol/L; and the calcium-channel blocker nicardipine, 1 micromol/L) for 30 minutes and then were grafted into the carotid arteries. Two weeks after surgery, vein graft samples were analyzed for vessel intimal and medial area, lumen diameter, and ECM composition. Molecular analysis using reverse transcription-polymerase chain reaction, Western immunoblotting, gelatin zymography, and reverse zymography were performed to study the expression and activation of MMP-2 and MMP-9, and tissue inhibitors of MMP (TIMP)-1 and TIMP-2.
  
  
  RESULTS
  Pressure distention irreversibly overstretched the porcine jugular vein and increased MMP-2 and MMP-9 proteolytic activity by 40% and 77%, respectively. Two weeks of vein grafting in the carotid arterial bed induced vessel wall thickening, ECM modification, and neointima formation, which were more pronounced in the distended grafts (P < .05) and accompanied by an increase in MMP expression and activity. Distended grafts demonstrated higher percentages of active MMP-9 (17.8% +/- 1.0%) and higher activities of latent (35.5% +/- 3.3%) and active MMP-2 (69.6% +/- 8.8%) than the pharmacologically treated grafts. Protein expression of TIMP-1 and TIMP-2 was downregulated after arterial grafting, but the pharmacologically treated grafts expressed significantly more TIMP-1 protein (by 36.8% +/- 4.1%) than the distended ones. The activities of TIMPs were markedly decreased after grafting, contributing to the upregulated MMP activity.
  
  
  CONCLUSIONS
  Pressure distention of vein grafts before implantation, compared with pharmacologic vasodilatation, stimulates neointima formation and augments MMP activities. Pharmacologic vasorelaxation may be clinically superior to distention in attenuating graft remodeling and possibly improving graft patency.
  
  
  CONCLUSIONS
  Autogenous vein bypasses are a common and effective method to treat occlusive disease. This study demonstrated that pressure distention, a common preparatory procedure in bypass surgery, upregulates extracellular matrix-degrading matrix metalloproteinases, which predisposes vein grafts to extensive remodeling and contributes to neointima formation and graft occlusion. The topical application of a combination of vasodilators to the vein graft before implantation may be clinically superior to pressure distention in attenuating graft remodeling and may possibly improve graft patency and reduce secondary surgical interventions.
authors.affiliation: James Hogg iCAPTURE Center, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Ada W Y
authors.initials: AW
authors.lastname: Chung
authors.forename: Pooja
authors.initials: P
authors.lastname: Rauniyar
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.forename: York N
authors.initials: YN
authors.lastname: Hsiang
authors.forename: Cornelis
authors.initials: C
authors.lastname: van Breemen
authors.forename: Elena B
authors.initials: EB
authors.lastname: Okon
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D015153:Blotting, Western; D016893:Carotid Stenosis / Q000601:surgery*; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D007150:Immunohistochemistry; D007601:Jugular Veins / Q000637:transplantation*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism*; D010643:Phenoxybenzamine / Q000494:pharmacology*; D011336:Probability; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D013552:Swine; D014021:Tissue Preservation; D016378:Tissue Transplantation / Q000379:methods; D014182:Transplantation, Autologous; D015854:Up-Regulation; D014656:Vascular Surgical Procedures / Q000379:methods*
chemical_list: D015415:Biomarkers; D010643:Phenoxybenzamine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9