This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Slepian, M. J. Articles by Whitesell, L. Search for Related Content PubMed PubMed Citation Articles by Slepian, M. J. Articles by Whitesell, L.

(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

This article has been cited by other articles:

				S. Abraham, N. Kogata, R. Fassler, and R. H. Adams Integrin {beta}1 Subunit Controls Mural Cell Adhesion, Spreading, and Blood Vessel Wall Stability Circ. Res., March 14, 2008; 102(5): 562 - 570. [Abstract] [Full Text] [PDF]

				E. H.J. Heerkens, L. Shaw, A. Ryding, G. Brooker, J. J. Mullins, C. Austin, V. Ohanian, and A. M. Heagerty {alpha}V Integrins Are Necessary for Eutrophic Inward Remodeling of Small Arteries in Hypertension Hypertension, February 1, 2006; 47(2): 281 - 287. [Abstract] [Full Text] [PDF]

				G.A. Stouffer, A. Pathak, R. Zhao, and J. Huang Down But Not Out: New Insights Into the Role of {alpha}V{beta}3 Integrins in Vascular Healing Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1309 - 1310. [Full Text] [PDF]

				A. M. Bernstein, R. S. Greenberg, L. Taliana, and S. K. Masur Urokinase Anchors uPAR to the Actin Cytoskeleton Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 2967 - 2977. [Abstract] [Full Text] [PDF]

				P. Stawowy, H. Kallisch, J. P. Veinot, A. Kilimnik, W. Prichett, S. Goetze, N. G. Seidah, M. Chretien, E. Fleck, and K. Graf Endoproteolytic Activation of {alpha}v Integrin by Proprotein Convertase PC5 Is Required for Vascular Smooth Muscle Cell Adhesion to Vitronectin and Integrin-Dependent Signaling Circulation, February 17, 2004; 109(6): 770 - 776. [Abstract] [Full Text] [PDF]

				B. J. Rybarczyk, S. O. Lawrence, and P. J. Simpson-Haidaris Matrix-fibrinogen enhances wound closure by increasing both cell proliferation and migration Blood, December 1, 2003; 102(12): 4035 - 4043. [Abstract] [Full Text] [PDF]

				M. Sajid, R. Zhao, A. Pathak, S. S. Smyth, and G. A. Stouffer {alpha}v{beta}3-Integrin antagonists inhibit thrombin-induced proliferation and focal adhesion formation in smooth muscle cells Am J Physiol Cell Physiol, November 1, 2003; 285(5): C1330 - C1338. [Abstract] [Full Text] [PDF]

				J.-M. Li, L. M. Fan, A. Shah, and G. Brooks Targeting {alpha}v{beta}3 and {alpha}5{beta}1 for gene delivery to proliferating VSMCs: synergistic effect of TGF-{beta}1 Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1123 - H1131. [Abstract] [Full Text] [PDF]

				T. Kanzaki and M. Otabe Latent Transforming Growth Factor-{beta} Binding Protein-1, a Component of Latent Transforming Growth Factor-{beta} Complex, Accelerates the Migration of Aortic Smooth Muscle Cells in Diabetic Rats Through Integrin-{beta}3 Diabetes, March 1, 2003; 52(3): 824 - 828. [Abstract] [Full Text] [PDF]

				M. Sun, M. A. Opavsky, D. J. Stewart, M. Rabinovitch, F. Dawood, W.-H. Wen, and P. P. Liu Temporal Response and Localization of Integrins {beta}1 and {beta}3 in the Heart After Myocardial Infarction: Regulation by Cytokines Circulation, February 25, 2003; 107(7): 1046 - 1052. [Abstract] [Full Text] [PDF]

				U. Kintscher, C. Lyon, S. Wakino, D. Bruemmer, X. Feng, S. Goetze, K. Graf, A. Moustakas, B. Staels, E. Fleck, et al. PPAR{alpha} Inhibits TGF-{beta}-Induced {beta}5 Integrin Transcription in Vascular Smooth Muscle Cells by Interacting With Smad4 Circ. Res., November 29, 2002; 91 (11): e35 - e44. [Abstract] [Full Text] [PDF]

				P. Dufourcq, T. Couffinhal, P. Alzieu, D. Daret, C. Moreau, C. Duplaa, and J. Bonnet Vitronectin is up-regulated after vascular injury and vitronectin blockade prevents neointima formation Cardiovasc Res, March 1, 2002; 53(4): 952 - 962. [Abstract] [Full Text] [PDF]

				E. P. Moiseeva Adhesion receptors of vascular smooth muscle cells and their functions Cardiovasc Res, December 1, 2001; 52(3): 372 - 386. [Abstract] [Full Text] [PDF]

				M. Lele, M. Sajid, N. Wajih, and G. A. Stouffer Eptifibatide and 7E3, but Not Tirofiban, Inhibit {alpha}v{beta}3 Integrin-Mediated Binding of Smooth Muscle Cells to Thrombospondin and Prothrombin Circulation, July 31, 2001; 104(5): 582 - 587. [Abstract] [Full Text] [PDF]

				G. G. Bishop, J. A. McPherson, J. M. Sanders, S. E. Hesselbacher, M. J. Feldman, C. A. McNamara, L. W. Gimple, E. R. Powers, S. A. Mousa, and I. J. Sarembock Selective {{alpha}}v{beta}3-Receptor Blockade Reduces Macrophage Infiltration and Restenosis After Balloon Angioplasty in the Atherosclerotic Rabbit Circulation, April 10, 2001; 103(14): 1906 - 1911. [Abstract] [Full Text] [PDF]

				T. J. A. Chico, J. Chamberlain, J. Gunn, N. Arnold, S. L. Bullens, T. R. Gadek, S. E. Francis, S. Bunting, M. Horton, L. Shepherd, et al. Effect of Selective or Combined Inhibition of Integrins {{alpha}}IIb{beta}3 and {{alpha}}v{beta}3 on Thrombosis and Neointima After Oversized Porcine Coronary Angioplasty Circulation, February 27, 2001; 103(8): 1135 - 1141. [Abstract] [Full Text] [PDF]

				K. L. Davenpeck, C. Marcinkiewicz, D. Wang, R. Niculescu, Y. Shi, J. L. Martin, and A. Zalewski Regional Differences in Integrin Expression : Role of {{alpha}}5{beta}1 in Regulating Smooth Muscle Cell Functions Circ. Res., February 16, 2001; 88(3): 352 - 358. [Abstract] [Full Text] [PDF]

				J. H Baron, E. P Moiseeva, D. P de Bono, K. R Abrams, and A. H Gershlick Inhibition of vascular smooth muscle cell adhesion and migration by c7E3 Fab (abciximab): a possible mechanism for influencing restenosis Cardiovasc Res, December 1, 2000; 48(3): 464 - 472. [Abstract] [Full Text] [PDF]

				N. Maitra, I. L. Flink, J. J. Bahl, and E. Morkin Expression of {alpha} and {beta} integrins during terminal differentiation of cardiomyocytes Cardiovasc Res, September 1, 2000; 47(4): 715 - 725. [Abstract] [Full Text] [PDF]

				G. Li, Y.-F. Chen, S. S. Kelpke, S. Oparil, and J. A. Thompson Estrogen Attenuates Integrin-{beta}3-Dependent Adventitial Fibroblast Migration After Inhibition of Osteopontin Production in Vascular Smooth Muscle Cells Circulation, June 27, 2000; 101(25): 2949 - 2955. [Abstract] [Full Text] [PDF]

				M. P. Bendeck, C. Irvin, M. Reidy, L. Smith, D. Mulholland, M. Horton, and C. M. Giachelli Smooth Muscle Cell Matrix Metalloproteinase Production Is Stimulated via {alpha}v{beta}3 Integrin Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1467 - 1472. [Abstract] [Full Text] [PDF]

				E Stringa, V Knauper, G Murphy, and J Gavrilovic Collagen degradation and platelet-derived growth factor stimulate the migration of vascular smooth muscle cells J. Cell Sci., January 6, 2000; 113(11): 2055 - 2064. [Abstract] [PDF]

				K. Kappert, G. Schmidt, G. Doerr, B. Wollert-Wulf, E. Fleck, and K. Graf Angiotensin II and PDGF-BB Stimulate {beta}1-Integrin-Mediated Adhesion and Spreading in Human VSMCs Hypertension, January 1, 2000; 35(1): 255 - 261. [Abstract] [Full Text] [PDF]

				A. Hassid, J. Yao, and S. Huang NO alters cell shape and motility in aortic smooth muscle cells via protein tyrosine phosphatase 1B activation Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H1014 - H1026. [Abstract] [Full Text] [PDF]

				P. Jones, F. Jones, B Zhou, and M Rabinovitch Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type I collagen is dependent upon a beta3 integrin-mediated mitogen-activated protein kinase pathway and a 122-base pair promoter element J. Cell Sci., January 2, 1999; 112(4): 435 - 445. [Abstract] [PDF]