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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

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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