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Thromb Haemost 2000; 84(04): 701-705
DOI: 10.1055/s-0037-1614090
Review Article
Schattauer GmbH

Role of α5β1 and αvβ3 Integrins on Smooth Muscle Cell Spreading and Migration in Fibrin Gels

Yuji Ikari
2   From the Department of Pathology, University of Washington, USA
,
Karen O. Yee
1   The Department of Molecular and Cellular Biology, University of Washington, USA
,
Stephen M. Schwartz
2   From the Department of Pathology, University of Washington, USA
› Author Affiliations
Further Information

Publication History

Received 15 December 1999

Accepted after revision 20 April 2000

Publication Date:
11 December 2017 (online)

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Summary

Fibrin is found at sites of vascular injury and is one of the major matrix ligands for β3 integrins. Blocking the β3 integrin on smooth muscle cell is hypothesized as a potential target to prevent restenosis because it could inhibit cell attachment and migration into fibrin provisional matrix. Human aortic smooth muscle cells (HNB18E6E7) spread stably in plasma gels within 24 h. Cell spreading was dramatically blocked by simultaneous use of α5β1 and αvβ3 integrin antibodies (P <0.0001), however, blocking of either integrin alone failed to inhibit spreading. GPenGRGDSPCA, which has been considered a specific αvβ3 antagonist, inhibited spreading at 500 µM, suggesting that the peptide blocked both α5β1 and αvβ3. Similarly, invasive migration into fibrin gels was blocked by simultaneous use of both α5β1 and αvβ3 antibodies, however, blocking of either integrin alone failed to effect cell migration. Another migration assay using transwell indicated similar results. In conclusion, both α5β1 and αvβ3 integrins are responsible for smooth muscle cell spreading and migration into fibrin gels. These data suggest that blocking β3 integrin alone would not affect smooth muscle cell interaction with fibrin.

Key words

Fibrinogen - RGD peptide - fibrin gel contraction
 

  • References

  • 1 Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators. Lancet 1994; 343: 881-6.
    CrossrefPubMedSearch in Google Scholar
  • 2 Aguirre FV, Topol EJ, Ferguson JJ, Anderson K, Blankenship JC, Heuser RR, Sigmon K, Taylor M, Gottlieb R, Hanovich G, Rosenberg M, Donohue TJ, Weisman HF, Califf RM. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. EPIC Investigators. Circulation 1995; 91: 2882-90.
    CrossrefPubMedSearch in Google Scholar
  • 3 Lincoff AM, Califf RM, Anderson KM, Weisman HF, Aguirre FV, Kleiman NS, Harrington RA, Topol EJ. Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. EPIC Investigators. Evaluation of 7E3 in Preventing Ischemic Complications. J Am Coll Cardiol 1997; 30: 149-56.
    CrossrefPubMedSearch in Google Scholar
  • 4 Moliterno DJ, Califf RM, Aguirre FV, Anderson K, Sigmon KN, Weisman HF, Topol EJ. Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (the EPIC trial). Evaluation of c7E3 Fab in the Prevention of Ischemic Complications trial. Am J Cardiol 1995; 75: 559-62.
    CrossrefPubMedSearch in Google Scholar
  • 5 Tcheng JE, Ellis SG, George BS, Kereiakes DJ, Kleiman NS, Talley JD, Wang AL, Weisman HF, Califf RM, Topol EJ. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in highrisk coronary angioplasty. Circulation 1994; 90: 1757-64.
    CrossrefPubMedSearch in Google Scholar
  • 6 Tcheng JE. Glycoprotein IIb/IIIa receptor inhibitors: putting the EPIC, IMPACT II, RESTORE, and EPILOG trials into perspective. Am J Cardiol 1996; 78: 35-40.
    PubMedSearch in Google Scholar
  • 7 Topol EJ. Prevention of cardiovascular ischemic complications with new platelet glycoprotein IIb/IIIa inhibitors. Am Heart J 1995; 130: 666-72.
    CrossrefPubMedSearch in Google Scholar
  • 8 Topol EJ, Ferguson JJ, Weisman HF, Tcheng JE, Ellis SG, Kleiman NS, Ivanhoe RJ, Wang AL, Miller DP, Anderson KM, Califf RM. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. EPIC Investigator Group. Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication. Jama 1997; 278: 479-84.
    CrossrefPubMedSearch in Google Scholar
  • 9 Coller BS, Anderson K, Weisman HF. New antiplatelet agents: platelet GPIIb/IIIa antagonists. Thromb Haemost 1995; 74: 302-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Hoshiga M, Alpers CE, Smith LL, Giachelli CM, Schwartz SM. Alpha-v beta-3 integrin expression in normal and atherosclerotic artery. Circ Res 1995; 77: 1129-35.
    CrossrefPubMedSearch in Google Scholar
  • 11 Felding-Habermann B, Ruggeri ZM, Cheresh DA. Distinct biological consequences of integrin alpha vs. alpha vs. J Biol Chem 1992; J Biol Chem 1992; 267: 5070-7.
    PubMedSearch in Google Scholar
  • 12 Choi ET, Engel L, Callow AD, Sun S, Trachtenberg J, Santoro S, Ryan US. Inhibition of neointimal hyperplasia by blocking alpha V beta 3 integrin with a small peptide antagonist GpenGRGDSPCA. J Vasc Surg 1994; 19: 125-34.
    CrossrefPubMedSearch in Google Scholar
  • 13 Matsuno H, Stassen JM, Moons L, Vermylen J, Hoylaerts MF. Neointima formation in injured hamster carotid artery is effectively prevented by the combination G4120 and quinapril. Thromb Haemost 1996; 76: 263-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Bosmans JM, Kockx MM, Vrints CJ, Bult H, De-Meyer GR, Herman AG. Fibrin(ogen) and von Willebrand factor deposition are associated with intimal thickening after balloon angioplasty of the rabbit carotid artery. Arterioscler Thromb Vasc Biol 1997; 17: 634-45.
    CrossrefPubMedSearch in Google Scholar
  • 15 Montalescot G, Ankri A, Vicaut E, Drobinski G, Grosgogeat Y, Thomas D. Fibrinogen after coronary angioplasty as a risk factor for restenosis. Circulation 1995; 92: 31-8.
    PubMedSearch in Google Scholar
  • 16 Courtman DW, Schwartz SM, Hart CE. Sequential injury of the rabbit abdominal aorta induces coagulation and luminal narrowing independent of intimal mass: extrinsic pathway inhibition inhibits luminal narrowing. Circ Res 1998; 82: 996-1006.
    CrossrefPubMedSearch in Google Scholar
  • 17 Yee KO, Rooney MM, Giachelli CM, Lord ST, Schwartz SM. Role of b1 and b3 integrins in human smooth muscle cell adhesion to and contraction of fibrin clots in vitro. Circ Res 1998; 83: 241-51.
    CrossrefPubMedSearch in Google Scholar
  • 18 Liaw L, Skinner MP, Raines EW, Ross R, Cheresh DA, Schwartz SM, Giachelli CM. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest 1995; 95: 713-24.
    CrossrefPubMedSearch in Google Scholar
  • 19 Perez-Reyes N, Halbert CL, Smith PP, Benditt EP, McDougall JK. Immortalization of primary human smooth muscle cells. Proc Natl Acad Sci USA 1992; 89: 1224-8.
    CrossrefPubMedSearch in Google Scholar
  • 20 Naito M, Nomura H, Iguchi A. Migration of cultured vascular smooth muscle cells into non-crosslinked fibrin gels. Thromb Res 1996; 84: 129-36.
    CrossrefPubMedSearch in Google Scholar
  • 21 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258: 1183-6.
    CrossrefPubMedSearch in Google Scholar
  • 22 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-5.
    CrossrefPubMedSearch in Google Scholar
  • 23 Meade TW, North WR, Chakrabarti R, Stirling Y, Haines AP, Thompson SG, Brozovi’e M. Haemostatic function and cardiovascular death: early results of a prospective study. Lancet 1980; 01: 1050-4.
    PubMedSearch in Google Scholar
  • 24 Bini A, Fenoglio Jr JJ, Mesa-Tejada R, Kudryk B, Kaplan KL. Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis. Use of monoclonal antibodies. Arteriosclerosis 1989; 09: 109-21.
    CrossrefPubMedSearch in Google Scholar
  • 25 Smith EB, Thompson WD. Fibrin as a factor in atherogenesis. Thromb Res 1994; 73: 1-19.
    CrossrefPubMedSearch in Google Scholar
  • 26 Smith EB. Fibrin deposition and fibrin degradation products in atherosclerotic plaques. Thromb Res 1994; 75: 329-35.
    CrossrefPubMedSearch in Google Scholar
  • 27 Gailit J, Clarke C, Newman D, Tonnesen MG, Mosesson MW, Clark RA. Human fibroblasts bind directly to fibrinogen at RGD sites through integrin alpha(v)beta3. Exp Cell Res 1997; 232: 118-26.
    CrossrefPubMedSearch in Google Scholar
  • 28 Smith RA, Mosesson MW, Rooney MM, Lord ST, Daniels AU, Gartner TK. The role of putative fibrinogen Aalpha-, Bbeta-, and GammaA-chain integrin binding sites in endothelial cell-mediated clot retraction. J Biol Chem 1997; 272: 22080-5.
    CrossrefPubMedSearch in Google Scholar
  • 29 Tanoue K, Katagiri Y, Suzuki H. Molecular mechanisms of fibrin gel clot retraction by platelets and cultured tumor cells. Pol J Pharmacol 1996; 48: 341-3.
    PubMedSearch in Google Scholar
  • 30 Schafer BM, Maier K, Eickhoff U, Todd RF, Kramer MD. Plasminogen activation in healing human wounds. Am J Pathol 1994; 144: 1269-80.
    PubMedSearch in Google Scholar
  • 31 Clark RA, Tonnesen MG, Gailit J, Cheresh DA. Transient functional expression of alphaVbeta 3 on vascular cells during wound repair. Am J Pathol 1996; 148: 1407-21.
    PubMedSearch in Google Scholar
  • 32 Henke CA, Roongta U, Mickelson DJ, Knutson JR, McCarthy JB. CD44- related chondroitin sulfate proteoglycan, a cell surface receptor implicated with tumor cell invasion, mediates endothelial cell migration on fibrinogen and invasion into a fibrin matrix. J Clin Invest 1996; 97: 2541-52.
    CrossrefPubMedSearch in Google Scholar
  • 33 Svee K, White J, Vaillant P, Jessurun J, Roongta U, Krumwiede M, Johnson D, Henke C. Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44. J Clin Invest 1996; 98: 1713-27.
    CrossrefPubMedSearch in Google Scholar
  • 34 Loike JD, Silverstein R, Wright SD, Weitz JI, Huang AJ, Silverstein SC. The role of protected extracellular compartments in interactions between leukocytes, and platelets, and fibrin/fibrinogen matrices. Ann N Y Acad Sci 1992; 667: 163-72.
    CrossrefPubMedSearch in Google Scholar
  • 35 Nachman RL, Leung LL, Kloczewiak M, Hawiger J. Complex formation of platelet membrane glycoproteins IIb and IIIa with the fibrinogen D domain. J Biol Chem 1984; 259: 8584-8.
    PubMedSearch in Google Scholar
  • 36 Marshall JF, Rutherford DC, McCartney AC, Mitjans F, Goodman SL, Hart IR. Alpha v beta 1 is a receptor for vitronectin and fibrinogen, and acts with alpha 5 beta 1 to mediate spreading on fibronectin. J Cell Sci 1995; 108: 1227-38.
    PubMedSearch in Google Scholar
  • 37 Suehiro K, Gailit J, Plow EF. Fibrinogen is a ligand for integrin alpha5 beta1 on endothelial cells. J Biol Chem 1997; 272: 5360-6.
    CrossrefPubMedSearch in Google Scholar
  • 38 Greiling D, Clark RAF. Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix. J Cell Sci 1997; 110: 861-70.
    PubMedSearch in Google Scholar
  • 39 Clyman RI, Goetzman BW, Chen YQ, Mauray F, Kramer RH, Pytela R, Schnapp LM. Changes in endothelial cell and smooth muscle cell integrin expression during closure of the ductus arteriosus: an immunohistochemical comparison of the fetal, preterm newborn, and full-term newborn rhesus monkey ductus. Pediatr Res 1996; 40: 198-208.
    CrossrefPubMedSearch in Google Scholar
  • 40 Geary RL, Nikkari ST, Wagner WD, Williams JK, Adams MR, Dean RH. Wound healing: a paradigm for lumen narrowing after arterial reconstruction. J Vasc Surg 1998; 27: 96-106.
    CrossrefPubMedSearch in Google Scholar
  • 41 Ruggiero F, Comte J, Cabanas C, Garrone R. Structural requirements for alpha 1 beta 1 and alpha 2 beta 1 integrin mediated cell adhesion to collagen V. J Cell Sci 1996; 109: 1865-74.
    PubMedSearch in Google Scholar
  • 42 Skinner MP, Raines EW, Ross R. Dynamic expression of alpha 1 beta 1 and alpha 2 beta 1 integrin receptors by human vascular smooth muscle cells. Alpha 2 beta 1 integrin is required for chemotaxis across type I collagencoated membranes. Am J Pathol 1994; 145: 1070-81.
    PubMedSearch in Google Scholar
  • 43 Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell 1996; 87: 1069-78.
    CrossrefPubMedSearch in Google Scholar
  • 44 Matsuno H, Stassen JM, Vermylen J, Deckmyn H. Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. Circulation 1994; 90: 2203-6.
    CrossrefPubMedSearch in Google Scholar
  • 45 Slepian MJ, Massia SP, Dehdashti B, Fritz A, Whitesell L. Beta-3 integrins rather than beta-1 integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration. Circulation 1998; 97: 1818-27.
    CrossrefPubMedSearch in Google Scholar
  • 46 Cardarelli PM, Cobb RR, Nowlin DM, Scholz W, Gorcsan F, Moscinski M, Yasuhara M, Chiang SL, Lobl TJ. Cyclic RGD peptide inhibits alpha 4 beta 1 interaction with connecting segment 1 and vascular cell adhesion molecule. J Biol Chem 1994; 269: 18668-73.
    PubMedSearch in Google Scholar
  • 47 Bilato C, Curto KA, Monticone RE, Pauly RR, White AJ, Crow MT. The inhibition of vascular smooth muscle cell migration by peptide and antibody antagonists of the alphavbeta3 integrin complex is reversed by activated calcium/calmodulin-dependent protein kinase II. J Clin Invest 1997; 100: 693-704.
    CrossrefPubMedSearch in Google Scholar
  • 48 Tselepis VH, Green LJ, Humphries MJ. An RGD to LDV motif conversion within the disintegrin kistrin generates an integrin antagonist that retains potency but exhibits altered receptor specificity. Evidence for a functional equivalence of acidic integrin-binding motifs. J Biol Chem 1997; 272: 21341-8.
    CrossrefPubMedSearch in Google Scholar
  • 49 Pierschbacher MD, Ruoslahti E. Influence of stereochemistry of the sequence Arg-Gly-Asp-Xaa on binding specificity in cell adhesion. J Biol Chem 1987; 262: 17294-8.
    PubMedSearch in Google Scholar