β 3 -Integrins Rather Than β 1 -Integrins Dominate Integrin-Matrix Interactions Involved in Postinjury Smooth Muscle Cell Migration

Abstract

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 β ₁ - and β ₃ -integrins. In this study, we examined the relative functional roles of β ₁ - and β ₃ -integrin–matrix interactions in postinjury SMC migration. Methods and Results —Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-β ₁ and anti-α _v β _3/5 antibodies (Abs) revealed expression of both β ₁ - and β ₃ -integrins, with β ₁ observed as linear streaks and β ₃ found in focal contacts. In a scrape-wound migration assay, anti-β 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. β ₃ -Blockade, however, via Abs (anti-β _3/5 35.7±4.5% of control, anti-β ₃ 61±12% of control, both P <.001) and cyclic RGD (0.5 mmol/L) (12±10% of control, P <.001) decreased migration. Neither β ₁ - nor β ₃ -inhibition altered postinjury [ ³ H]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 β 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 ×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 β ₃ -blockade via cRGD limited migration (0.8±0.8 versus 12.8±4.4 SMCs per ×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, β ₃ - rather than β 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 (β ₃ )–matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.