Directed migration of smooth muscle cells to engineer plaque-resistant vein grafts.
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.
Amabile
Philippe G
PG
Department of Cardiovascular and Interventional Radiology, Stanford University School of Medicine, California, USA.
Wang
David S
DS
Kao
Edward Y
EY
Lee
Jane
J
Elkins
Christopher J
CJ
Yuksel
Eser
E
Hilfiker
Paul R
PR
Waugh
Jacob M
JM
Dake
Michael D
MD
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
D010959:Tissue Plasminogen Activator