VEGF and inhibitors of TGFβ type-I receptor kinase synergistically promote blood-vessel formation by inducing α5-integrin expression
Copyright policy )VEGF and inhibitors of TGFβ type-I receptor kinase synergistically promote blood-vessel formation by inducing α5-integrin expression
Vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGFβ) are potent regulators of angiogenesis. How VEGF and TGFβ signaling pathways crosstalk is not well understood. Therefore, we analyzed the effects of the TGFβ type-I-receptor inhibitors (SB-431542 and LY-2157299) and VEGF on endothelial cell (EC) function and angiogenesis. We show that SB-431542 dramatically enhances VEGF-induced formation of EC sheets from fetal mouse metatarsals. Sub-optimal doses of VEGF and SB-431542 synergistically induced EC migration and sprouting of EC spheroids, whereas overexpression of a constitutively active form of TGFβ type-I receptor had opposite effects. Using quantitative PCR, we demonstrated that VEGF and SB-431542 synergistically upregulated the mRNA expression of genes involved in angiogenesis, including the integrins α5 and β3. Specific downregulation of α5-integrin expression or functional blocking of α5 integrin with a specific neutralizing antibody inhibited the cooperative effect of VEGF and SB-431542 on EC sprouting. In vivo, LY-2157299 induced angiogenesis and enhanced VEGF- and basic-fibroblast-growth-factor-induced angiogenesis in a Matrigel-plug assay, whereas adding an α5-integrin-neutralizing antibody to the Matrigel selectively inhibited this enhanced response. Thus, induction of α5-integrin expression is a key determinant by which inhibitors of TGFβ type-I receptor kinase and VEGF synergistically promote angiogenesis.
- University of Iceland Iceland
- Leiden University Medical Center Netherlands
Gene Expression Profiling, Integrin beta3, Endothelial Cells, Neovascularization, Physiologic, Drug Synergism, Dioxoles, Integrin alpha5, Protein Serine-Threonine Kinases, Drug Combinations, Mice, Fetus, Cell Movement, Neutralization Tests, Benzamides, Animals, Humans, Biological Assay, Collagen, Laminin, Protein Kinase Inhibitors
Gene Expression Profiling, Integrin beta3, Endothelial Cells, Neovascularization, Physiologic, Drug Synergism, Dioxoles, Integrin alpha5, Protein Serine-Threonine Kinases, Drug Combinations, Mice, Fetus, Cell Movement, Neutralization Tests, Benzamides, Animals, Humans, Biological Assay, Collagen, Laminin, Protein Kinase Inhibitors
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