title: Directed migration of smooth muscle cells to engineer plaque-resistant vein grafts.
abstract: OBJECTIVE
  To test the hypothesis that controlled perivascular release of tissue plasminogen activator (tPA) can generate cleaved extracellular matrix (ECM) chemotactic gradients to guide the migration of vascular smooth muscle cells (SMCs) away from the lumen, thereby limiting neointima formation.
  
  
  METHODS
  This hypothesis was tested in rabbit models in which the perivascular surface of vein bypass grafts was treated with microspheres releasing tPA (MS-tPA), microspheres containing no drug (MS-blank), or phosphate buffered saline (PBS). Vein graft segments harvested after 7 days were then evaluated for elastin content, proliferating SMCs, intima-to-media (I/M) ratio, and inflammation; late impact on neointima formation was also examined.
  
  
  RESULTS
  The 7-day results demonstrated cleaved elastin gradients and proliferating SMCs that assumed a more peripheral distribution in the MS-tPA group than MS-blank and PBS controls (p<0.05). At 28 days, vein grafts treated with MS-tPA showed a mean I/M ratio (0.35+/-0.04) that was 63.5% lower than PBS controls (0.96+/-0.07, p<0.005) and 43.5% lower than MS-blank specimens (0.62+/-0.08, p<0.05).
  
  
  CONCLUSIONS
  Perivascular release of tPA modifies ECM gradients, directionally guides SMC migration away from the lumen, and limits neointima formation.
authors.affiliation: Department of Cardiovascular and Interventional Radiology, Stanford University School of Medicine, California, USA.
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Amabile
authors.forename: David S
authors.initials: DS
authors.lastname: Wang
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Kao
authors.forename: Jane
authors.initials: J
authors.lastname: Lee
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Elkins
authors.forename: Eser
authors.initials: E
authors.lastname: Yuksel
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hilfiker
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Waugh
authors.forename: Michael D
authors.initials: MD
authors.lastname: Dake
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D008297:Male; D008863:Microspheres; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011817:Rabbits; D012501:Saphenous Vein / Q000637:transplantation*; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology*; D014656:Vascular Surgical Procedures
chemical_list: D010959:Tissue Plasminogen Activator