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Lactadherin promotes VEGF-dependent neovascularization

Nature Medicine volume 11, pages 499–506 (2005)Cite this article

Abstract

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 αvβ3 and αvβ5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced αvβ3- and αvβ5-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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Figure 1: Vascular expression of lactadherin.
Figure 2: Generation of lactadherin-deficient mice.
Figure 3: Role of lactadherin in VEGF-induced angiogenesis.
Figure 4: Role of lactadherin in VEGF-induced postischemic neovascularization.
Figure 5: Role of lactadherin in VEGF–induced signaling.
Figure 6: Lactadherin can promote angiogenesis.

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Acknowledgements

The authors thank INSERM, Institut Curie, European Community (grant QLRT-2001-00093) and Ligue Nationale contre le Cancer for funding; H. Laurell and H. Prats (INSERM U397, Toulouse, France) for kind gift of bFGF expression plasmid; K. Mitchell and W. Skarnes (Wellcome Trust, Cambridge, UK) for providing the ES cell line (see http://baygenomics.ucsf.edu). INSERM U689 and Cardiovascular Research Institute of Mastricht are partners of the European Vascular Genomics Network (EVGN), a Network of Excellence granted by the European Commission (contract No. LSHM-CT-2003-503254) and the contribution of S. Heeneman was undertaken in the context of EVGN.

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Author notes

  1. Jean-Sébastien Silvestre and Clotilde Théry: These authors contributed equally to this work.

Authors and Affiliations

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

    Jean-Sébastien Silvestre, Jacques Boddaert, Olivier Blanc-Brude, Michel Clergue, Micheline Duriez, Régine Merval, Bernard Lévy, Alain Tedgui & Ziad Mallat

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

    Clotilde Théry & Sebastian Amigorena

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

    Ghislaine Hamard & Christophe Houbron

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

    Barbara Aguilar & Alain Delcayre

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

    Radia Tamarat

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

    Sylvia Heeneman

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  1. Jean-Sébastien Silvestre
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Corresponding author

Correspondence to Ziad Mallat.

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Supplementary information

Supplementary Fig. 1

Generation of lactadherin-deficient mice. (PDF 100 kb)

Supplementary Fig. 2

Lactadherin and post-ischemic neovascularization. (PDF 143 kb)

Supplementary Fig. 3

Dose-dependent effect of lactadherin antibody administration. (PDF 110 kb)

Supplementary Fig. 4

Role of lactadherin in bFGF pro-angiogenic effect. (PDF 132 kb)

Supplementary Fig. 5

Putative model of lactadherin pro-angiogenic signaling. (PDF 96 kb)

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Silvestre, JS., Théry, C., Hamard, G. et al. Lactadherin promotes VEGF-dependent neovascularization. Nat Med 11, 499–506 (2005). https://doi.org/10.1038/nm1233

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