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Published online before print October 19, 2006

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(Journal of Leukocyte Biology. 2007;81:557-566.)
© 2007 by Society for Leukocyte Biology

Mechanisms underlying TGF-ß1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis

Seong-Hyun Jeon^*, Byung-Chul Chae^*, Hyun-A Kim^*, Goo-Young Seo^*, Dong-Wan Seo^*, Gie-Taek Chun^*, Nam-Soo Kim^*, Se-Won Yie^*, Woo-Hyeon Byeon^*, Seok-Hyun Eom^*, Kwon-Soo Ha, Young-Myeong Kim and Pyeung-Hyeun Kim^*,,1

^* Department of Molecular Bioscience, School of Bioscience and Biotechnology, and
Vascular System Research Center, Kangwon National University, Chunchon, Korea

¹ Correspondence: Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chunchon 200-701, Korea. E-mail: phkim{at}kangwon.ac.kr

TGF-ß induces vascular endothelial growth factor (VEGF), a potent angiogenic factor, at the transcriptional and protein levels in mouse macrophages. VEGF secretion in response to TGF-ß1 is enhanced by hypoxia and by overexpression of Smad3/4 and hypoxia-inducible factor-1/ß (HIF-1/ß). To examine the transcriptional regulation of VEGF by TGF-ß1, we constructed mouse reporters driven by the VEGF promoter. Overexpression of HIF-1/ß or Smad3/4 caused a slight increase of VEGF promoter activity in the presence of TGF-ß1, whereas cotransfection of HIF-1/ß and Smad3/4 had a marked effect. Smad2 was without effect on this promoter activity, whereas Smad7 markedly reduced it. Analysis of mutant promoters revealed that the one putative HIF-1 and two Smad-binding elements were critical for TGF-ß1-induced VEGF promoter activity. The relevance of these elements was confirmed by chromatin immunoprecipitation assay. p300, which has histone acetyltransferase activity, augmented transcriptional activity in response to HIF-1/ß and Smad3/4, and E1A, an inhibitor of p300, inhibited it. TGF-ß1 also increased the expression of fetal liver kinase-1 (Flk-1), a major VEGF receptor, and TGF-ß1 and VEGF stimulated pro-matrix metalloproteinase 9 (MMP-9) and active-MMP-9 expression, respectively. The results from the present study indicate that TGF-ß1 can activate mouse macrophages to express angiogenic mediators such as VEGF, MMP-9, and Flk-1.

Key Words: MMP-9 • HUVEC • promoter

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