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(Circulation. 1998;97:1818-1827.)
© 1998 American Heart Association, Inc.

Basic Science Reports

ß₃-Integrins Rather Than ß₁-Integrins Dominate Integrin-Matrix Interactions Involved in Postinjury Smooth Muscle Cell Migration

Marvin J. Slepian, MD; Stephen P. Massia, PhD; Behrooz Dehdashti, PhD; Anne Fritz, BS; ; Luke Whitesell, MD

From the University Heart Center, University of Arizona, Tucson.

Correspondence to Marvin J. Slepian, MD, University Heart Center, University of Arizona, PO Box 245037, 1501 N Campbell Ave, Tucson, AZ 85724. E-mail slepian{at}u.arizona.edu

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 ß₁- and ß₃-integrins. In this study, we examined the relative functional roles of ß₁- and ß₃-integrin–matrix interactions in postinjury SMC migration.

Methods and Results—Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-ß₁ and anti-_vß_3/5 antibodies (Abs) revealed expression of both ß₁- and ß₃-integrins, with ß₁ observed as linear streaks and ß₃ found in focal contacts. In a scrape-wound migration assay, anti-ß₁ 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. ß₃-Blockade, however, via Abs (anti-ß_3/5 35.7±4.5% of control, anti-ß₃ 61±12% of control, both P<.001) and cyclic RGD (0.5 mmol/L) (12±10% of control, P<.001) decreased migration. Neither ß₁- nor ß₃-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 ß₁-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 ß₃-blockade via cRGD limited migration (0.8±0.8 versus 12.8±4.4 SMCs per x600 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, ß₃- rather than ß₁-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 (ß₃)–matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.

Key Words: integrins • restenosis • cell adhesion molecules

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