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 cell migration. SMCs express both β₁- and β₃-integrins. In this study, we examined the relative functional roles of β₁- and β₃-integrin-matrix interactions in postinjury SMC migration. Methods and Results - Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-β₁ and anti-α(v)β₃/₅ antibodies (Abs) revealed expression of both β₁- andβ₃- integrins, with β₁ observed as linear streaks and β₃ found in focal contacts. In a scrape-wound migration assay, anti-β₁ 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. β₃-Blockade, however, via Abs (anti-β₃/₅ 35.7 ± 4.5% of control, anti-β₃ 61 ± 12% of control, both P < .001) and cyclic RGD (0.5 mmol/L) (12 ± 10% of control, P < .001) decreased migration. Neither β₁- nor β₃-inhibition altered postinjury [³H]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 β₁-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 x 600 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 β₃-blockade via cRGD limited migration (0.8 ± 0.8 versus 12.8 ± 4.4 SMCs per x 600 field [control], P < .01) and thickening (I/M area ratio, 0.004 ± 0.008 versus 1.179 ± 0.324 [control], P < .01). Conclusions - In postinjury migrating SMCs, β₃- rather than β₁-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 (/33)-matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.