Published online before print April 10, 2003, doi: 10.1161/01.RES.0000071345.76095.07
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Submitted on December 12, 2002
Revised on March 31, 2003
Accepted on April 1, 2003
Blockade of Vascular Smooth Muscle Cell Proliferation and Intimal Thickening After Balloon Injury by the Sulfated Oligosaccharide PI-88. Phosphomannopentaose Sulfate Directly Binds FGF-2, Blocks Cellular Signaling, and Inhibits Proliferation
Douglas J. Francis ;
From the Division of Immunology and Genetics (D.J.F., C.R.P., K.J.B., W.B.C., C.N.C.), John Curtin School of Medical Research, Australian National University, Canberra; Centre for Research in Vascular Biology (M.M., J.A.B., I.P.H., J.H.C., G.R.C.), School of Biomedical Science, University of Queensland, Brisbane; and the Centre for Thrombosis and Vascular Research (F.S.S., H.C.L., C.N.C., L.M.K.), University of New South Wales and the Department of Hematology, The Prince of Wales Hospital, Sydney, Australia.
* To whom correspondence should be addressed. E-mail: L.Khachigian{at}unsw.edu.au.
Percutaneous transluminal coronary angioplasty is a frequently used interventional technique to reopen arteries that have narrowed because of atherosclerosis. Restenosis, or renarrowing of the artery shortly after angioplasty, is a major limitation to the success of the procedure and is due mainly to smooth muscle cell accumulation in the artery wall at the site of balloon injury. In the present study, we demonstrate that the antiangiogenic sulfated oligosaccharide, PI-88, inhibits primary vascular smooth muscle cell proliferation and reduces intimal thickening 14 days after balloon angioplasty of rat and rabbit arteries. PI-88 reduced heparan sulfate content in the injured artery wall and prevented change in smooth muscle phenotype. However, the mechanism of PI-88 inhibition was not merely confined to the antiheparanase activity of this compound. PI-88 blocked extracellular signal-regulated kinase-1/2 (ERK1/2) activity within minutes of smooth muscle cell injury. It facilitated FGF-2 release from uninjured smooth muscle cells in vitro, and super-released FGF-2 after injury while inhibiting ERK1/2 activation. PI-88 inhibited the decrease in levels of FGF-2 protein in the rat artery wall within 8 minutes of injury. PI-88 also blocked injury-inducible ERK phosphorylation, without altering the clotting time in these animals. Optical biosensor studies revealed that PI-88 potently inhibited (Ki 10.3 nmol/L) the interaction of FGF-2 with heparan sulfate. These findings show for the first time the capacity of this sulfated oligosaccharide to directly bind FGF-2, block cellular signaling and proliferation in vitro, and inhibit injury-induced smooth muscle cell hyperplasia in two animal models. As such, this study demonstrates a new role for PI-88 as an inhibitor of intimal thickening after balloon angioplasty. The full text of this article is available online at http://www.circresaha.org.
Key words: phosphomannopentaose sulfate • heparanase inhibitor • smooth muscle cells • neointima formation • balloon angioplasty
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