Lactadherin promotes VEGF-dependent neovascularization

J.-S. Silvestre (1) , C. Théry (2) , G. Hamard (3) , J. Boddaert (1) , B. Aguilar (4) , A. Delcayre (4) , C. Houbron (3) , R. Tamarat (5) , O. Blanc-Brude (1) , S. Heeneman (6) , M. Clergue (1) , M. Duriez (1) , R. Merval (1) , B. Lévy (1) , A. Tedgui (1) , S. Amigorena (2) , Z. Mallat (1)

1 Centre de Recherche Cardiovasculaire de Lariboisiere
2 Immunité et cancer
3 UMR_S567 / UMR 8104 - Institut Cochin
4 Anosys Inc
5 IRSN - Institut de Radioprotection et de Sûreté Nucléaire
6 CARIM - Cardiovascular Research Institute Maastricht

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 αbβ5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced αbβ3- 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.

Mots clés: alphaVbeta5 integrin; binding protein; integrin; integrin binding protein; lactadherin; neutralizing antibody; protein kinase B; unclassified drug; vasculotropin; vitronectin receptor; angiogenesis; animal cell; animal experiment; animal model; animal tissue; article; controlled study; endothelium cell; female; leg ischemia; male; mouse; nonhuman; pathophysiology; priority journal; protein binding; protein expression; protein phosphorylation; protein protein interaction; signal transduction; vascularization; Analysis of Variance; Angiogenesis Inducing Agents; Animals; Antigens; Surface; Blotting; Southern; Crosses; Genetic; Female; Genetic Vectors; Humans; Integrin alphaVbeta3; Ischemia; Mice; Inbred C57BL; Milk Proteins; Muscle; Skeletal; Neovascularization; Physiologic; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Vascular Endothelial Growth Factor A; Animalia

Domaines: Sciences du Vivant [q-bio]

J.-S. Silvestre, C. Théry, G. Hamard, J. Boddaert, B. Aguilar, et al.. Lactadherin promotes VEGF-dependent neovascularization. Nature Medicine, 2005, 11 (5), pp.499-506. ⟨10.1038/nm1233⟩. ⟨hal-03041351⟩