The Role of α_vβ₃ Integrins in Vascular Healing

Summary

α_vβ₃ integrins play an important role in vascular healing. Vascular injury is a stimulus for expression of α_vβ₃ by vascular cells and, among other effects, α_vβ₃ integrins function in the adhesion of activated platelets to endothelium, white cell/endothelium interactions, plateletmediated thrombin generation, fibrin clot retraction by nucleated cells, smooth muscle cell (SMC) migration and proliferation, vascular cell apoptosis, and vascular remodeling. There are ten different animal models in which treatment with α_vβ₃ antagonists reduced the vascular response, including (neo)intima formation, after mechanical injury. These studies, along with mechanistic data derived from cell culture studies, provide compelling evidence that α_vβ₃ integrins are involved in vascular repair processes. The challenge is to develop a therapeutic agent that will prove effective in reducing restenosis in humans following percutaneous coronary intervention (PCI).

Keywords

Victronectin receptor - angioplasty - vascular smooth muscle

• References

• 1 Coller BS. A new murine monoclonal antibody reports an activationdependent change in the conformation and/or microenvironment of the platelet GP IIb/IIIa complex. J Clin Invest 1985; 76: 101-8.
• 2 Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999; 353: 227-31.
• 3 Tam SH, Sassoli PM, Jordan RE, Nakada MT. Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and α_{v 3} integrins. Circulation 1998; 98: 1085-91.
• 4 Lele M, Sajid M, Wajih N, Stouffer GA. Eptifibatide and 7E3, but not tiro- fiban, inhibit α_vβ₃ integrin-mediated binding of smooth muscle cells to thrombospondin and prothrombin. Circulation 2001; 104: 582-7.
• 5 Baron JH, Moiseeva EP, de Bono DP, Abrams KR, Gershlick AH. Inhibition of vascular smooth muscle cell adhesion and migration by c7E3 Fab (abciximab): a possible mechanism for influencing restenosis. Cardiovasc Res 2000; 48: 464-72.
• 6 Lincoff AM, Topol EJ. Overview of the glycoprotein IIb/IIIa inhibitor interventional trials. In: Platelet glycoprotein IIb/IIIa inhibitors in cardiovascular disease. Lincoff AM, Topol EJ. (eds). Totowa, NJ: Humana Press; 1999: 169-97.
• 7 Stouffer GA, Hu Z, Sajid M, Li H, Jin G, Nakada MT, Hanson SR, Runge MS. β₃ integrins are upregulated following vascular injury and mediate proliferation of cultured smooth muscle cells. Circulation 1998; 97: 907-15.
• 8 Srivatsa SS, Fitzpatrick LA, Tsao PW, Reilly TM, Holmes Jr. DR, Schwartz RS, Mousa SA. Selective α_vβ₃ integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury: evidence for the functional importance of integrin α_vβ₃ and osteopontin expression during neointima formation. Cardiovasc Res 1997; 36: 408-28.
• 9 van der Zee R, Murohara T, Passeri J, Kearney M, Cheresh DA, Isner JM. Reduced intimal thickening following α_vβ₃ blockade is associated with smooth muscle cell apoptosis. Cell Adhes Commun 1998; 06: 371-9.
• 10 Slepian MJ, Massia SP, Dehdashti B, Fritz A, Whitesell L. β₃-integrins rather than β₁-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration. Circulation 1998; 97: 1818-27.
• 11 Choi ET, Engel L, Callow AD, Sun S, Trachtenberg J, Santoro S, Ryan US. Inhibition of neointimal hyperplasia by blocking α_vβ₃ integrin with a small peptide antagonist GpenGRGDSPCA. J Vasc Surg 1994; 19: 125-34.
• 12 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.
• 13 Nichols TC, du Laney T, Zheng B, Bellinger DA, Nickols GA, Engleman W, Clemmons DR. Reduction in atherosclerotic lesion size in pigs by α_vβ₃ inhibitors is associated with inhibition of insulin-like growth factor-1mediated signaling. Circ Res 1999; 85: 1040-5.
• 14 Coleman KR, Braden GA, Willingham MC, Sane DC. Vitaxin, a humanized monoclonal antibody to the vitronectin receptor (α_vβ₃), reduces neointimal hyperplasia and total vessel area after balloon injury in hypercholesterolemic rabbits. Circ Res 1999; 84: 1268-76.
• 15 Chico TJA, Chamberlain J, Gunn J, Arnold N, Bullens SL, Gadek TR, Francis SE, Bunting S, Horton M, Shepherd L, Lipari MT, Quan C, Knolle J, Stilz HU, Peyman A, Crossman DC. Effect of selective or combined inhibition of integrins α_IIbβ₃ and α_vβ₃ on thrombosis and neointima after oversized porcine coronary angioplasty. Circulation 2001; 103: 1135-41.
• 16 Eliceiri BP, Cheresh DA. The role of α_v integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest 1999; 103: 1227-30.
• 17 Byzova TV, Rabbani R, D’Souza SE, Plow EF. Role of integrin α_vβ₃ in vascular biology. Thromb Haemost 1998; 80: 726-34.
• 18 Suehiro K, Smith JW, Plow EF. The ligand recognition specificity of β₃ integrins. J Biol Chem 1996; 271: 10365-71.
• 19 Byzova TV, Plow EF. Activation of α_vβ₃ on vascular cells controls recognition of prothrombin. J Cell Biol 1998; 143: 2081-92.
• 20 Pampori N, Hato T, Stupack DG, Aidoudi S, Cheresh DA, Nemerow GR, Shattil SJ. Mechanisms and consequences of affinity modulation of integrin α_vβ₃ detected with a novel patch-engineered monovalent ligand. J Biol Chem 1999; 274: 21609-16.
• 21 Bennett JS, Chan C, Vilaire G, Mousa SA, DeGrado WF. Agonist-activated α_vβ₃ on platelets and lymphocytes binds to the matrix protein osteopontin. J Biol Chem 1997; 272: 8137-40.
• 22 Byzova TV, Goldman CK, Pampori N, Thomas KA, Bett A, Shattil SJ, Plow EF. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 2000; 06: 851-60.
• 23 Corjay MH, Diamond SM, Schlingmann KL, Gibbs SK, Stoltenborg JK, Racanelli AL. α_vβ₃, α_vβ₅, and osteopontin are coordinately upregulated at early time points in a rabbit model of neointima formation. J Cell Bioch 1999; 75: 492-504.
• 24 Bendeck MP, Irvin C, Reidy M, Smith L, Mulholland D, Horton M, Giachelli CM. Smooth muscle cell matrix metalloproteinase production is stimulated via α_vβ₃ integrin. Arterioscler Thromb Vasc Biol 2000; 20: 1467-72.
• 25 Hoshiga M, Alpers CE, Smith LL, Giachelli CM, Schwartz SM. α_vβ₃ integrin expression in normal and atherosclerotic artery. Circ Res 1995; 77: 1129-35.
• 26 Liaw L, Lindner V, Schwartz SM, Chambers AF, Giachelli CM. Osteopontin and β₃ integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp-dependent endothelial migration in vitro. Circ Res 1995; 77: 665-72.
• 27 Miano JM, Vlasic N, Tota RR, Stemerman MB. Smooth muscle cell immediate-early gene and growth factor activation follows vascular injury. Arterioscler Thromb 1993; 13: 211-9.
• 28 Sajid M, Hu Z, Guo H, Li H, Stouffer GA. Vascular expression of integrinassociated protein and thrombospondin increase following mechanical injury. J Investig Med 2001; 49: 398-405.
• 29 Hatton MW, Southward SM, Serebrin SD, Kulczycky M, Blajchman MA. Catabolism of rabbit prothrombin in rabbits: uptake of prothrombin by the aorta wall before and after a de-endothelializing injury in vivo. J Lab Clin Med 1995; 126: 521-9.
• 30 Bauters C, Marotte F, Hamon M, Oliviero P, Farhadian F, Robert V, Samuel JL, Rappaport L. Accumulation of fetal fibronectin mRNAs after balloon denudation of rabbit arteries. Circulation 1995; 92: 904-11.
• 31 Kageyama S, Yamamoto H, Yoshimoto R. Anti-human von Willebrand factor monoclonal antibody AJvW-2 prevents thrombus deposition and neointima formation after balloon injury in guinea pigs. Arterioscler Thromb Vasc Biol (Online) 2000; 20: 2303-8.
• 32 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.
• 33 Dufourcq P, Louis H, Moreau C, Daret D, Boisseau MR, Lamaziere JM, Bonnet J. Vitronectin expression and interaction with receptors in smooth muscle cells from human atheromatous plaque. Arterioscler Thromb Vasc Biol 1998; 18: 168-76.
• 34 Nakamura T, Ruiz-Lozano P, Lindner V, Yabe D, Taniwaki M, Furukawa Y, Kobuke K, Tashiro K, Lu Z, Andon NL, Schaub R, Matsumori A, Sasayama S, Chien KR, Honjo T. DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries. J Biol Chem 1999; 274: 22476-83.
• 35 Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin α_vβ₃ . Cell 1996; 85: 683-93.
• 36 Keenan RM, Lago MA, Miller WH, Ali FE, Cousins RD, Hall LB, Hwang SM, Jakas DR, Kwon C, Louden C, Nguyen TT, Ohlstein EH, Rieman DJ, Ross ST, Samanen JM, Smith BR, Stadel J, Takata DT, Vickery L, Yuan CC, Yue TL. Discovery of an imidazopyridine-containing 1,4-benzodiazepine nonpeptide vitronectin receptor (α_vβ₃) antagonist with efficacy in a restenosis model. Bioorg Med Chem Letters 1998; 08: 3171-6.
• 37 Bishop GG, McPherson JA, Sanders JM, Hesselbacher SE, Feldman MJ, McNamara CA, Gimple LW, Powers ER, Mousa SA, Sarembock IJ. Selective α_vβ₃-receptor blockade reduces macrophage infiltration and restenosis after balloon angioplasty in the atherosclerotic rabbit. Circulation 2001; 103: 1906-11.
• 38 Deitch JS, Williams JK, Adams MR, Fly CA, Herrington DM, Jordan RE, Nakada MT, Jakubowski JA, Geary RL. Effects of β₃-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates. Arterioscler Thromb Vasc Biol 1998; 18: 1730-7.
• 39 Wu CH, Chen YC, Hsiao G, Lin CH, Liu CM, Sheu JR. Mechanisms involved in the inhibition of neointimal hyperplasia by abciximab in a rat model of balloon angioplasty. Thromb Res 2001; 101: 127-38.
• 40 Skinner MP, Raines EW, Ross R. Dynamic expression ofα₁β₁ and α₂β₁ integrin receptors by human vascular smooth muscle cells. Am J Pathol 1994; 145: 1070-81.
• 41 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. J Clin Invest 1995; 95: 713-24.
• 42 Sajid M, Lele M, Stouffer GA. Autocrine thrombospondin partially mediates TGF-beta1 – induced proliferation of vascular smooth muscle cells. Am J Physiol – Heart & Circulatory Physiology 2000; 279: H2159-H65.
• 43 Yue TL, McKenna PJ, Ohlstein EH, Farach-Carson MC, Butler WT, Johanson K, McDevitt P, Feuerstein GZ, Stadel JM. Osteopontin-stimulated vascular smooth muscle cell migration is mediated by β₃ integrin. Exp Cell Res 1994; 214: 459-64.
• 44 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 α_vβ₃ integrin complex is reversed by activated calcium/calmodulin-dependent protein kinase II. J Clin Invest 1997; 100: 693-704.
• 45 Brown SL, Lundgren CH, Nordt T, Fujii S. Stimulation of migration of human aortic smooth muscle cells by vitronectin: implications for atherosclerosis. Cardiovasc Res 1994; 28: 1815-20.
• 46 Patel MK, Lymn JS, Clunn GF, Hughes AD. Thrombospondin-1 is a powerful mitogen and chemoattractant for human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17: 2107-14.
• 47 Clemmons DR, Horvitz G, Engleman W, Nichols T, Moralez A, Nickols GA. Synthetic α_vβ₃ antagonists inhibit insulin-like growth factor-I-stimulated smooth muscle cell migration and replication. Endocrinology 1999; 140: 4616-21.
• 48 Janat MF, Argraves WS, Liau G. Regulation of vascular smooth muscle cell integrin expression by transforming growth factor β₁ and by platelet-derived growth factor-BB. J Cell Physiol 1992; 151: 588-95.
• 49 Witzenbichler B, Kureishi Y, Luo Z, Le Roux A, Branellec D, Walsh K. Regulation of smooth muscle cell migration and integrin expression by the Gax transcription factor. J Clin Invest 1999; 104: 1469-80.
• 50 Itoh H, Nelson PR, Mureebe L, Horowitz A, Kent KC. The role of integrins in saphenous vein vascular smooth muscle cell migration. J Vasc Surg 1997; 25: 1061-9.
• 51 Vuori K, Ruoslahti E. Association of insulin receptor substrate-1 with integrins. Science 1994; 266: 1576-8.
• 52 Mawatari K, Liu B, Kent KC. Activation of integrin receptors is required for growth factor-induced smooth muscle cell dysfunction. J Vasc Surg 2000; 31: 375-81.
• 53 Babic AM, Chen CC, Lau LF. Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin α_vβ₃, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 1999; 19: 2958-66.
• 54 Paik JH, Chae S, Lee MJ, Thangada S, Hla T. Sphingosine 1-phosphateinduced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of α_vβ₃and beta1-containing integrins. J Biol Chem 2001; 276: 11830-7.
• 55 Kim S, Harris M, Varner JA. Regulation of integrin α_vβ₃-mediated endothelial cell migration and angiogenesis by integrin ; ₅β₁ and protein kinase A. J Biol Chem 2000; 275: 33920-8.
• 56 Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), α_vβ₃ integrin, and GPIbalpha. J Exp Med 1998; 187: 329-39.
• 57 Dardik R, Varon D, Tamarin I, Zivelin A, Salomon O, Shenkman B, Savion N. Homocysteine and oxidized low density lipoprotein enhanced platelet adhesion to endothelial cells under flow conditions: distinct mechanisms of thrombogenic modulation. Thromb Haemost 2000; 83: 338-44.
• 58 Gawaz M, Neumann FJ, Dickfeld T, Reininger A, Adelsberger H, Gebhardt A, Schomig A. Vitronectin receptor (α_vβ₃) mediates platelet adhesion to the luminal aspect of endothelial cells: implications for reperfusion in acute myocardial infarction. Circulation 1997; 96: 1809-18.
• 59 Reininger AJ, Agneskirchner J, Bode PA, Spannagl M, Wurzinger LJ. c7E3 Fab inhibits low shear flow modulated platelet adhesion to endothelium and surface-absorbed fibrinogen by blocking platelet GP IIb/IIIa as well as endothelial vitronectin receptor – results from patients with acute myocardial infarction and healthy controls. Thromb Haemost 2000; 83: 217-23.
• 60 Piali L, Hammel P, Uherek C, Bachmann F, Gisler RH, Dunon D, Imhof BA. CD31/PECAM-1 is a ligand for α_vβ₃ integrin involved in adhesion of leukocytes to endothelium. J Cell Biol 1995; 130: 451-60.
• 61 Chiba R, Nakagawa N, Kurasawa K, Tanaka Y, Saito Y, Iwamoto I. Ligation of CD31 (PECAM-1) on endothelial cells increases adhesive function of α_vβ₃ integrin and enhances β₁ integrin-mediated adhesion of eosinophils to endothelial cells. Blood 1999; 94: 1319-29.
• 62 Imhof BA, Weerasinghe D, Brown EJ, Lindberg FP, Hammel P, Piali L, Dessing M, Gisler R. Cross talk between α_vβ₃ and α₄β₁ integrins regulates lymphocyte migration on vascular cell adhesion molecule 1. Eur J Immunol 1997; 27: 3242-52.
• 63 Thompson RD, Wakelin MW, Larbi KY, Dewar A, Asimakopoulos G, Horton MA, Nakada MT, Nourshargh S. Divergent effects of platelet-endothelial cell adhesion molecule-1 and β₃ integrin blockade on leukocyte transmigration in vivo. J Immunol 2000; 165: 426-34.
• 64 Meisel SR, Shapiro H, Radnay J, Neuman Y, Khaskia AR, Gruener N, Pauzner H, David D. Increased expression of neutrophil and monocyte adhesion molecules LFA-1 and Mac-1 and their ligand ICAM-1 and VLA-4 throughout the acute phase of myocardial infarction: possible implications for leukocyte aggregation and microvascular plugging. J Am Coll Cardiol 1998; 31: 120-5.
• 65 Mickelson JK, Ali MN, Kleiman NS, Lakkis NM, Chow TW, Hughes BJ, Smith CW. Chimeric 7E3 Fab (ReoPro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty. J Am Coll Cardiol 1999; 33: 97-106.
• 66 Lincoff AM, Kereiakes DJ, Mascelli MA, Deckelbaum LI, Barnathan ES, Patel KK, Frederick B, Nakada MT, Topol EJ. Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation 2001; 104: 163-7.
• 67 Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999; 285: 1028-32.
• 68 Schneller M, Vuori K, Ruoslahti E. α_vβ₃ integrin associates with activated insulin and PDGFβ receptors and potentiates the biological activity of PDGF. EMBO J 1997; 16: 5600-7.
• 69 Erb L, Liu J, Ockerhausen J, Kong Q, Garrad RC, Griffin K, Neal C, Krugh B, Santiago-Perez LI, Gonzalez FA, Gresham HD, Turner JT, Weisman GA. An RGD sequence in the P2Y(2) receptor interacts with α_vβ₃ integrins and is required for G(o)-mediated signal transduction. J Cell Biol 2001; 153: 491-501.
• 70 Gao AG, Lindberg FP, Dimitry JM, Brown EJ, Frazier WA. Thrombospondin modulates α_vβ₃ function through integrin-associated protein. J Cell Biol 1996; 135: 533-44.
• 71 Wang XQ, Frazier WA. The thrombospondin receptor CD47 (IAP) modulates and associates with α₂β₁ integrin in vascular smooth muscle cells. Mol Biol Cell 1998; 09: 865-74.
• 72 Chen D, Asahara T, Krasinski K, Witzenbichler B, Yang J, Magner M, Kearney M, Frazier WA, Isner JM, Andres V. Antibody blockade of thrombospondin accelerates reendothelialization and reduces neointima formation in balloon-injured rat carotid artery. Circulation 1999; 100: 849-54.
• 73 Gao A-G, Lindberg FP, Finn MB, Blystone SD, Brown EJ, Frazier WA. Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin. J Biol Chem 1996; 271: 21-4.
• 74 Dorahy DJ, Thorne RF, Fecondo JV, Burns GF. Stimulation of platelet activation and aggregation by a carboxyl-terminal peptide from thrombospondin binding to the integrin-associated protein receptor. J Biol Chem 1997; 272: 1323-30.
• 75 Calderwood DA, Shattil SJ, Ginsberg MH. Integrins and Actin Filaments: Reciprocal Regulation of Cell Adhesion and Signaling. J Biol Chem 2000; 275: 22607-10.
• 76 Bartfeld NS, Pasquale EB, Geltosky JE, Languino LR. The α_vβ₃ integrin associates with a 190-kDa protein that is phosphorylated on tyrosine in response to platelet-derived growth factor. J Biol Chem 1993; 268: 17270-6.
• 77 Jenkins AL, Nannizzi-Alaimo L, Silver D, Sellers JR, Ginsberg MH, Law DA, Phillips DR. Tyrosine phosphorylation of the β₃ cytoplasmic domain mediates integrin-cytoskeletal interactions. J Biol Chem 1998; 273: 13878-85.
• 78 Sajid M, Hu Z, Lele M, Stouffer GA. Protein complexes involving α_vβ₃ integrins, nonmuscle myosin heavy chain-A and focal adhesion kinase form in thrombospondin-treated smooth muscle cells. J Invest Med 2000; 48: 190-7.
• 79 Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM. NF-kappaB mediates α_vβ₃ integrin-induced endothelial cell survival. J Cell Biol 1998; 141: 1083-93.
• 80 Stromblad S, Becker JC, Yebra M, Brooks PC, Cheresh DA. Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin α_vβ₃ during angiogenesis. J Clin Invest 1996; 98: 426-33.
• 81 Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 2000; 105: 21-34.
• 82 Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA. Integrin α_vβ₃ antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79: 1157-64.
• 83 Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin α_vβ₃ . Clin Cancer Res 2000; 06: 3056-61.