Lactadherin promotes VEGF-dependent neovascularization.
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.
Silvestre
Jean-Sébastien
JS
Cardiovascular Research Center INSERM U689 Lariboisière, Université Paris 7, Hôpital Lariboisière, 41 bvd de la chapelle, 75475 Paris cedex 10, France.
Théry
Clotilde
C
Hamard
Ghislaine
G
Boddaert
Jacques
J
Aguilar
Barbara
B
Delcayre
Alain
A
Houbron
Christophe
C
Tamarat
Radia
R
Blanc-Brude
Olivier
O
Heeneman
Sylvia
S
Clergue
Michel
M
Duriez
Micheline
M
Merval
Régine
R
Lévy
Bernard
B
Tedgui
Alain
A
Amigorena
Sebastian
S
Mallat
Ziad
Z
D000704:Analysis of Variance; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D015139:Blotting, Southern; D003433:Crosses, Genetic; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D043925:Angiogenesis Inducing Agents; D000954:Antigens, Surface; D039302:Integrin alphaVbeta3; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt