Published online before print October 19, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0806517

Received for publication August 16, 2006.
Revised September 18, 2006.
Accepted for publication September 25, 2006.

Article

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

Sung-Ki Chun ^*, 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 ^*@

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

^@ To whom correspondence should be addressed. E-mail: phkim{at}kangwon.ac.kr.

Abstract

TGF- 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-1 is enhanced by hypoxia and by overexpression of Smad3/4 and hypoxia-inducible factor-1/ (HIF-1/). To examine the transcriptional regulation of VEGF by TGF-1, we constructed mouse reporters driven by the VEGF promoter. Overexpression of HIF-1/ or Smad3/4 caused a slight increase of VEGF promoter activity in the presence of TGF-1, whereas cotransfection of HIF-1/ 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-1-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/ and Smad3/4, and E1A, an inhibitor of p300, inhibited it. TGF-1 also increased the expression of fetal liver kinase-1 (Flk-1), a major VEGF receptor, and TGF-1 and VEGF stimulated pro-matrix metalloproteinase 9 (MMP-9) and active-MMP-9 expression, respectively. The results from the present study indicate that TGF-1 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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