title: VCL, an antagonist of the platelet GP1b receptor, markedly inhibits platelet adhesion and intimal thickening after balloon injury in the rat.
abstract: BACKGROUND
  Arterial injury is immediately followed by platelet adhesion at the site of injury, a process that requires the interaction of subendothelial von Willebrand factor with the platelet GP1b receptor. VCL, a recombinant von Willebrand factor GP1b binding domain, inhibits platelet binding to von Willebrand factor. The aim of this study was to determine whether VCL inhibits platelet adhesion at the site of arterial injury and affects neointimal thickening after injury in rats.
  
  
  RESULTS
  Sprague-Dawley rats were randomized to receive VCL, 4 mg/kg bolus followed by a continuous infusion of 2 mg.kg-1.h-1 for 72 hours, or an identical volume of saline. Balloon injury of the femoral artery was performed 15 minutes after the initial bolus injection of VCL. Scanning electron microscopy performed 1 and 3 days after injury indicated that VCL-treated rats had > 80% reduction in the number of platelets adherent to the vessel wall at the site of injury compared with controls (P < .003). Histological examination at day 14 showed that, compared with controls, VCL-treated rats had a 60% reduction in the intima-media ratio (0.21 +/- 0.03 versus 0.53 +/- 0.06, P = .001) and a reduced luminal area stenosis (12 +/- 3% versus 38 +/- 10%, P = .04). At 28 days after injury, there was no rebound of neointimal thickening in VCL-treated rats (intima-media ratio, 0.19 +/- 0.04; luminal stenosis, 17 +/- 5%). The difference between VCL-treated rats and control rats persisted but was attenuated (intima-media ratio, 0.19 +/- 0.04 versus 0.28 +/- 0.1, P = .162; luminal stenosis, 17 +/- 5% versus 31 +/- 5%, P = .058) as neointimal thickening regressed in untreated rats. With the use of proliferating cell nuclear antigen immunohistochemistry on day 3, VCL had no effect on smooth muscle cell (SMC) proliferation.
  
  
  CONCLUSIONS
  Antagonism of the platelet GP1b receptor by VCL profoundly decreased platelet deposition at the site of balloon injury in the rat femoral artery. This effect was associated with a persistent reduction in neointimal thickening. The lack of effect of VCL on SMC proliferation suggests that the decrease in neointimal thickening may have been mediated through inhibition of SMC migration and/or modulation of the extracellular matrix.
authors.affiliation: Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zahger
authors.forename: M C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: L I
authors.initials: LI
authors.lastname: Garfinkel
authors.forename: P K
authors.initials: PK
authors.lastname: Shah
authors.forename: J S
authors.initials: JS
authors.lastname: Forrester
authors.forename: J
authors.initials: J
authors.lastname: Regnstrom
authors.forename: J
authors.initials: J
authors.lastname: Yano
authors.forename: B
authors.initials: B
authors.lastname: Cercek
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000648:ultrastructure; D010446:Peptide Fragments / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects* / Q000648:ultrastructure; D014841:von Willebrand Factor / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C032193:glycoprotein receptor GPIb-IX; D014841:von Willebrand Factor; C090953:von Willebrand factor (504-728)