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Article
Nature Medicine  11, 499 - 506 (2005)
Published online: 17 April 2005; | doi:10.1038/nm1233

Lactadherin promotes VEGF-dependent neovascularization

Jean-Sébastien Silvestre1, 7, Clotilde Théry2, 7, Ghislaine Hamard3, Jacques Boddaert1, Barbara Aguilar4, Alain Delcayre4, Christophe Houbron3, Radia Tamarat5, Olivier Blanc-Brude1, Sylvia Heeneman6, Michel Clergue1, Micheline Duriez1, Régine Merval1, Bernard Lévy1, Alain Tedgui1, Sebastian Amigorena2 & Ziad Mallat1

1  Cardiovascular Research Center INSERM U689 Lariboisière; Université Paris 7; Hôpital Lariboisière, 41 bvd de la chapelle, 75475 Paris cedex 10, France.

2  INSERM U653 et Institut Curie, 26 rue d'Ulm, 75249 Paris cedex 05, France.

3  Institut Cochin, INSERM U567, Plate-forme de recombinaison homologue, 24 rue du Faubourg St Jacques, 75014 Paris.

4  Anosys, Inc., 1014 Hamilton Court, Menlo Park, California 94025, USA.

5  Institut de Radioprotection et de SÛreté Nucléaire, 92262 Fontenay aux Roses cedex, France.

6  Department of Pathology, Cardiovascular Research Institute Maastricht, 6229 HX Maastricht, The Netherlands.

7  These authors contributed equally to this work.

Correspondence should be addressed to Ziad Mallat mallat@larib.inserm.fr
Vascular endothelial growth factor (VEGF)-induced blood vessel growth is involved in both physiological and pathological angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGF-dependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with alphavbeta3 and alphavbeta5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced alphavbeta3- and alphavbeta5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGF-dependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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