Inhibition of Leucocyte and Platelet Adhesion Reduces Neointimal Hyperplasia after Arterial Injury

Summary

Restenosis following coronary angioplasty is thought to result from migration and proliferation of medial smooth muscle cells. However, the factors that initiate this proliferation are still unknown. In a rabbit model of carotid artery injury, we tested the hypothesis that activated platelets and leucocytes might contribute to the development of neointimal hyperplasia. Following arterial injury, rabbits received either no treatment, R15.7, a monoclonal antibody against the leucocyte CD ll/CD 18 adhesion complex, aurintricarboxylic acid (ATA), a sub stance that inhibits platelet glycoprotein Ib-von Willebrand factor interaction, or the combination of R15.7 and ATA. After 21 days, the extent of neointimal hyperplasia was evaluated by planimetry on histological arterial sections. The area of neointima averaged 0.51 ±0.07 mm² in control animals and it was significantly reduced by administrationof either R15.7 or ATA alone to 0.12 ± 0.05 and 0.20 ±0.01 mm², respectively (p <0.05 vs controls for both groups). The animals that received the combination of R15.7 and ATA showed a further reduction in neointimal hyperplasia, as compared to animals that received ATA alone (p <0.05 vs ATA alone). These data indicate that platelets and leucocytes play animportant role in the pathophysi ology of neointimal hyperplasia in this experimental model. Interven tions that reduce platelet and leucocyte adhesion to vessel wall might have beneficial effects in reducing restenosis following coronary angioplasty.

• References

• 1 Schwartz RS, Holmes DR, Topol EJ. The restenosis paradigm reviseted: An alternative proposal for cellular mechanisms. J Am Coll Cardiol 1992; 20: 1284-1293
• 2 Liu MW, Roubin GS, King III SB. Restenosis after coronary angioplasty: Potential biologic determinants and the role of intimal hyperplasia. Circulation 1989; 79: 1374-1387
• 3 Shirotani M, Yui Y, Kaway C. Restenosis after coronary angioplasty: Pathogenesis of neointimal thickening initiated by endothelial loss. Endothelium 1993; 01: 05-22
• 4 Ma X-L, Tsao PS, Lefer AM. Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion. J Clin Invest 1991; 88: 1237-1243
• 5 Strony J, Phillips M, Brands D, Moake J, Adelman B. Aurintricarboxylic acid in a canine model of coronary artery thrombosis. Circulation 1990; 81: 1106-1114
• 6 Golino P, Ambrosio G, Ragni M, Pascucci I, Triggiani M, Oriente A, McNatt J, Buja LM, Conderelli M, Chiariello M, Willerson JT. Short-term and long-term role of platelet activating factor as a mediator of in vivo platelet aggregation. Circulation 1993; 88: 1205-1214
• 7 Golino P, Ragni M, Cirillo P, Pascucci I, Ezekowitz MD, Pawashe A, Scognamiglio A, Pace L, Condorelli M, Chiariello M. Aurintricarboxylic acid reduces platelet deposition in stenosed and endothelially injured rabbit carotid arteries more effectively than other antiplatelet interventions. Thromb Haemost. 1997. in press
• 8 Golino P, Cappelli-Bigazzi M, Ambrosio G, Ragni M, Russolillo E, Condorelli M, Chiariello M. Endothelium-derived relaxing factor modulates platelet aggregation in an in vivo model of recurrent platelet activation. CircRes 1992; 71: 1447-1453
• 9 Hynes RO. Integrins: a family of cell surface receptors. Cell 1987; 48: 549-554
• 10 Allan G, Bhattacherjee P, Brook CD, Read NG, Parke AJ. Myeloperoxidase activity as a quantitative marker of polymorphonuclear leucocyte accumulation into an experimental myocardial infarct – The effects of ibuprofen on infarct size and polymorphonuclear leucocyte accumulation. J Cardio-vasc Pharmacol 1985; 07: 1154-1160
• 11 Benezra M, Ben-Sasson SA, Regan J, Chang M, Bar-Shavit R, Vlodavsky I. Antiproliferative activity to vascular smooth muscle cells and receptor binding of heparin-mimicking polyaromatic anionic compounds. Aterio-scler Thromb 1994; 14: 1992-1999
• 12 Dempsey EC, McMutry IF, O’Brien RF. Protein kinase C activation allows pulmonary artery smooth muscle cells to proliferate to hypoxia. Am J Physiol 1991; 260: 136-145
• 13 Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J 1994; 8: 504-512
• 14 Morisaki N, Takahashi K, Shiina R, Zenibayashi M, Otabe M, Yoshida M, Saito Y. Platelet-derived growth factor is a potent stimulator of expression of intracellular adhesion molecule-1 in human arterial smooth muscle cells. Biochem Biophys Res Commun 1994; 200: 612-668
• 15 Ikeda U, Ikeda M, Seino Y, Takahashi M, Kashaara T, Kano S, Shimada K. Expression of intercellular adhesion molecule-1 on rat vascular smooth muscle cells by pro-inflammatory cytokines. Atherosclerosis 1993; 104: 61-68
• 16 Couffinhal T, Duplaa C, Moreau C, Lamaziere JM, Bonnet J. Regulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular smooth muscle cells. Circ Res 1994; 74: 225-234
• 17 Tanaka H, Sukhova GK, Swanson SJ, Clinton SK, Ganz P, Cybulsky MI, Libby P. Sustained activation of vascular cells and leucocytes in the rabbit aorta after ballon injury. Circulation 1993; 88: 1788-1803
• 18 Goldberg ID, Stemerman MB. Vascular permeation of platelet factor 4 after endothelial injury. Science 1980; 209: 611-612
• 19 Willerson JT, Sheng-Kun Y, McNatt J, Benedict CR, Anderson HV, Golino P, Murphree SS, Buja LM. Frequency and severity of cyclic flow alterations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury. Proc Natl Acad Sci USA 1991; 88: 10624-10628
• 20 Fingerle J, Johnson R, Clowes AW, Majesky MA, Reidy MA. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci USA 1989; 86: 8412-8416
• 21 Azrin MA, Ling FS, Chen Q, Pawashe A, Migliaccio F, Homer R, Todd M, Ezekowitz MD. Preparation, characterization, and evaluation of a monoclonal antibody against the rabbit platelet glycoprotein Ilb/IIIa in an experimental angioplasty model. Circ Res 1994; 75: 268-277
• 22 Baumgartner HR, Muggli R. Adhesion and aggregation: Morphological demonstration and quantitation in vivo and in vitro. In: Platelets in biology and pathology. Gordon JL. ed Elsevier; Amsterdam: 1976. pp 23-60
• 23 Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell 1986; 46: 155-169
• 24 Zahger D, Fishbein MC, Garfinkel LI, Shah PK, Forrester JS, Regnstrom J, Yano J, Cercek B. VCL, an antagonist of the platelet Gp lb receptor, markedly inhibits platelet adhesion and intimal thickening after balloon injury in the rat. Circulation 1995; 92: 1269-1273
• 25 Stiles CD, Pledger WJ, Tucker RW, Martin RG, Scher CD. Regulation of the Balb/C-3T3 cell cycle: effects of growth factors. J Supramol Struct 1980; 13: 489-499
• 26 Kling D, Fingerle J, Harlan JM. Inhibition of leukocyte extravasation with a monoclonal antibody to CD 18 during formation of experimental intimal thickening in rabbit carotid arteries. Arterioscler Thromb 1992; 12: 997-1007
• 27 Molossi S, Elices M, Arrhenius T, Diaz R, Coulber C, Rabinovitch M. Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts. J Clin Invest 1995; 95: 2601-2610