β3-integrins rather than β1-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration

Background-Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin-extracellular matrix interactions are essential for call migration. SMCs express both beta(1)- and beta(3)-integrins. In this study, we examined the relative functional roles of beta(1)- and beta(3)-integrin-matrix interactions in postinjury SMC mi,oration. Methods and Results-Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-Pi and anti-alpha(v) beta(3/5) antibodies (Abs) revealed expression of both beta(1)- and beta(3)-integrins, with beta(1) observed as linear streaks and beta(3) found in focal contacts. In a scrape-wound migration assay, anti-beta(1) Abs (92.0 +/- 10.7% of control, P=.1) and 0.5 mmol/L linear RGD (105+/-5% of control, P=.2) did not alter SMC migration at 48 hours after injury. beta(3)-Blockade, however, via Abs (anti-beta(3/5) 35.7+/-4.5% of control, anti-beta(3) 61+/-12% of control, both P<.001) and cyclic RGD (0.5 mmol/L) (12+/-10% of control, P<.001) decreased migration. Neither beta(1)- nor beta(3)-inhibition altered postinjury [H-3]thymidine incorporation. In the rat carotid injury model, local adventitial polymer-based delivery of radiolabeled linear or cyclic RGD led to uptake and retention of label, for both peptides, over a 72-hour period after injury. Local arterial wall beta(1)-blockade via polymer-based delivery of Linear RGD had no effect on SMC migration at 4.5 days (11.5+/-3.2 versus 12.8 SMCs per X600 field [control], P=.6) or on neointimal thickening at 14 days (I/M area ratio, 0.664+/-0.328 versus 1.179+/-0.324 [control], P=.6) after injury. In contrast, local beta(3)-blockade via cRGD limited migration (0.8+/-0.8 versus 12.8+/-4.4 SMCs per X600 field [control], P<.01) and thickening (J/M area ratio, 0.004+/-0.008 versus 1.179+/-0.324 [control], P<.01). Conclusions-In postinjury migrating SMCs, beta(3)- rather than beta(1)-integrin-matrix interactions are of greater functional significance in adhesive processes essential for SMC migration in vitro and in vivo. Blockade of dominant SMC integrin (beta(3))-matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.