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First published online 25 August 2009
doi: 10.1242/jcs.048942

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VEGF and inhibitors of TGFβ type-I receptor kinase synergistically promote blood-vessel formation by inducing 5-integrin expression

Zhen Liu¹, Kazuki Kobayashi¹, Maarten van Dinther¹, Sandra H. van Heiningen^1,2, Gudrun Valdimarsdottir³, Theo van Laar¹, Marion Scharpfenecker^1,*, Clemens W. G. M. Löwik⁴, Marie-José Goumans¹, Peter ten Dijke^1, and Evangelia Pardali¹

¹ Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, The Netherlands
² Department of Human Genetics, Leiden University Medical Center, The Netherlands
⁴ Endocrinology and Metabolic Diseases, Leiden University Medical Center, The Netherlands
³ Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Iceland

Author for correspondence (p.ten_dijke{at}lumc.nl)

Accepted 23 June 2009

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 5 and β3. Specific downregulation of 5-integrin expression or functional blocking of 5 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 5-integrin-neutralizing antibody to the Matrigel selectively inhibited this enhanced response. Thus, induction of 5-integrin expression is a key determinant by which inhibitors of TGFβ type-I receptor kinase and VEGF synergistically promote angiogenesis.

Key words: Angiogenesis, Endothelial cell, Integrin, Signaling, SB-431542, TGFβ, VEGF

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