Endothelial alpha3beta1-integrin represses pathological angiogenesis and sustains endothelial-VEGF.
Integrin alpha3beta1 is a major receptor for laminin. The expression levels of laminins-8 and -10 in the basement membrane surrounding blood vessels are known to change during tumor angiogenesis. Although some studies have suggested that certain ligands of alpha3beta1 can affect angiogenesis either positively or negatively, either a direct in vivo role for alpha3beta1 in this process or its mechanism of action in endothelial cells during angiogenesis is still unknown. Because the global genetic ablation of alpha3-integrin results in an early lethal phenotype, we have generated conditional-knockout mice where alpha3 is deleted specifically in endothelial cells (ec-alpha3-/-). Here we show that ec-alpha3-/- mice are viable, fertile, and display enhanced tumor growth, elevated tumor angiogenesis, augmented hypoxia-induced retinal angiogenesis, and increased vascular endothelial growth factor (VEGF)-mediated neovascularization ex vivo and in vivo. Furthermore, our data provide a novel method by which an integrin may regulate angiogenesis. We show that alpha3beta1 is a positive regulator of endothelial-VEGF and that, surprisingly, the VEGF produced by endothelial cells can actually repress VEGF-receptor 2 (Flk-1) expression. These data, therefore, identify directly that endothelial alpha3beta1 negatively regulates pathological angiogenesis and implicate an unexpected role for low levels of endothelial-VEGF as an activator of neovascularization.
da Silva
Rita Graça
RG
Adhesion and Angiogenesis Laboratory, Barts Institute of Cancer, Queen Mary University of London, London, UK.
Tavora
Bernardo
B
Robinson
Stephen D
SD
Reynolds
Louise E
LE
Szekeres
Charles
C
Lamar
John
J
Batista
Sílvia
S
Kostourou
Vassiliki
V
Germain
Mitchel A
MA
Reynolds
Andrew R
AR
Jones
Dylan T
DT
Watson
Alan R
AR
Jones
Janet L
JL
Harris
Adrian
A
Hart
Ian R
IR
Iruela-Arispe
M Luisa
ML
Dipersio
C Michael
CM
Kreidberg
Jordan A
JA
Hodivala-Dilke
Kairbaan M
KM
D000818:Animals; D015153:Blotting, Western; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D039201:Integrin alpha3beta1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2