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First published online 4 January 2005
doi: 10.1242/jcs.01613

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Elastin-derived peptides enhance angiogenesis by promoting endothelial cell migration and tubulogenesis through upregulation of MT1-MMP

Arnaud Robinet^1,*, Abdel Fahem^1,*, Jean-Hubert Cauchard¹, Eric Huet¹, Loïc Vincent², Sandrine Lorimier³, Franck Antonicelli¹, Claudine Soria², Michel Crepin⁴, William Hornebeck¹ and Georges Bellon^1,

¹ Laboratoire de Biochimie et Biologie Moléculaire, CNRS UMR 6198, IFR 53 Biomolécules, Faculté de Médecine, Université de Reims Champagne-Ardenne, 51 rue Cognacq Jay, 51095 Reims CEDEX, France
² Groupe de Recherche MERCI, EA CNRS 2122, Faculté de Médecine et de Pharmacie, 22 Boulevard Gambetta, 78183 Rouen, France
³ Laboratoire Biomatériaux, INSERM EMI, IFR 53 Biomolécules, Faculté d'Odontologie, Université de Reims-Champagne-Ardenne, 1 rue du Maréchal Juin, 51095 Reims CEDEX, France
⁴ Laboratoire Hémostase, Endothélium et Angiogenèse, INSERM U553, Hôpital St Louis, 1 Avenue Claude Vellefaux, 75475 Paris CEDEX 10, France

Author for correspondence (e-mail: georges.bellon{at}univ-reims.fr)

Accepted 22 October 2004

Elastin-derived peptides display a wide range of biological activities in a number of normal and transformed cells but their involvement in angiogenesis has not been reported. In the present study, we show that -elastin and VGVAPG hexapeptide elastin motif accelerated angiogenesis in the chick chorio-allantoic membrane in an in vivo model. They also stimulated pseudotube formation from human vascular and microvascular endothelial cells in the matrigel and collagen models as well as cell migration in an in vitro wound healing assay. Confocal and scanning electron microscopy analyses revealed the main reorganization of actin filaments mediated by elastin-derived peptides and changes in cell shape that correlated with a decrease of the cell form factor determined by computerized image analysis. Such elastin-derived peptide effects were attributed to upregulation of proMT1-MMP and proMMP-2 expression and activation at both the mRNA and protein levels. Batimastat, an inhibitor of furin convertase and TIMP-2, but not TIMP-1, totally abolished the influence of elastin-derived peptides (EDPs) on cell migration and tubulogenesis, thus favoring the involvement of MT1-MMP in such processes. To assess its contribution to EDP-mediated angiogenesis further, we used a small interfering RNA (siRNA) approach for specifically silencing MT1-MMP in human microvascular endothelial cells. Four sets of 21 bp siRNA duplexes targeting MT1-MMP mRNA were synthesized by in vitro transcription. Two of them proved to inhibit MT1-MMP expression efficiently but did not affect MT2-, MT3- and MT5-MMP expression. Seventy-two hours after transfection with 25 nM siRNAs EDP-induced MT1-MMP expression at the mRNA and protein levels was decreased fourfold. In parallel, proMMP-2 activation was inhibited. A scrambled siRNA, used as a negative control, had no effect. Finally, the effect of elastin peptides on pseudotube formation in MT1-MMP-siRNA transfected cells was totally abolished. These data emphasise the crucial role of MT1-MMP in the elastin-induced angiogenic phenotype of endothelial cells.

Key words: Angiogenesis, Elastin, Matrix metalloproteinase, Elastin receptor, siRNA

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