TY - JOUR
T1 - Endothelial α3β1-integrin represses pathological angiogenesis and sustains endothelial-VEGF
AU - da Silva, Rita Graça
AU - Tavora, Bernardo
AU - Robinson, Stephen D.
AU - Reynolds, Louise E.
AU - Szekeres, Charles
AU - Lamar, John
AU - Batista, Sílvia
AU - Kostourou, Vassiliki
AU - Germain, Mitchel A.
AU - Reynolds, Andrew R.
AU - Jones, Dylan T.
AU - Watson, Alan R.
AU - Jones, Janet L.
AU - Harris, Adrian
AU - Hart, Ian R.
AU - Iruela-Arispe, M. Luisa
AU - DiPersio, C. Michael
AU - Kreidberg, Jordon A.
AU - Hodivala-Dilke, Kairbaan M.
PY - 2010/9
Y1 - 2010/9
N2 - Integrin a3ß1 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 a3ß1 can affect angiogenesis either positively or negatively, either a direct in vivo role for a3ß1 in this process or its mechanism of action in endothelial cells during angiogenesis is still unknown. Because the global genetic ablation of a3-integrin results in an early lethal phenotype, we have generated conditional-knockout mice where a3 is deleted specifically in endothelial cells (ec-a3-/-). Here we show that ec-a3-/- 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 a3ß1 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 a3ß1 negatively regulates pathological angiogenesis and implicate an unexpected role for low levels of endothelial-VEGF as an activator of neovascularization.
AB - Integrin a3ß1 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 a3ß1 can affect angiogenesis either positively or negatively, either a direct in vivo role for a3ß1 in this process or its mechanism of action in endothelial cells during angiogenesis is still unknown. Because the global genetic ablation of a3-integrin results in an early lethal phenotype, we have generated conditional-knockout mice where a3 is deleted specifically in endothelial cells (ec-a3-/-). Here we show that ec-a3-/- 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 a3ß1 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 a3ß1 negatively regulates pathological angiogenesis and implicate an unexpected role for low levels of endothelial-VEGF as an activator of neovascularization.
U2 - 10.2353/ajpath.2010.100043
DO - 10.2353/ajpath.2010.100043
M3 - Article
SN - 1525-2191
VL - 177
SP - 1534
EP - 1548
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -