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First published online 3 April 2007
doi: 10.1242/jcs.000679

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Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells

¹ Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan
² Division of Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan
³ Mouse Genome Technology Center, Mitsubishi Kagaku Institute of Life Sciences, Tokyo 194-8511, Japan
⁴ Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan
⁵ National Institute for Basic Biology, Okazaki 444-8585, Japan
⁶ Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Japan
⁷ Daiichi Fine Chemical Corporation, 530 Chokeiji, Takaoka, Toyama 933-8511, Japan
⁸ Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Japan
⁹ Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

^* Author for correspondence (e-mail: mseiki{at}ims.u-tokyo.ac.jp)

Accepted 18 March 2007

The membrane-anchored matrix metalloproteinase MT1-MMP (also known as Mmp14) plays a key role in the angiogenic process, but the mechanisms underlying its spatiotemporal regulation in the in vivo setting have not been defined. Using whole-mount immunohistochemical analysis and the lacZ gene inserted into the Mmp14 gene, we demonstrate that MT1-MMP vascular expression in vivo is confined largely to the sprouting tip of neocapillary structures where endothelial cell proliferation and collagen degradation are coordinately localized. During angiogenesis in vitro, wherein endothelial cells are stimulated to undergo neovessel formation in the presence or absence of accessory mural cells, site-specific MT1-MMP expression is shown to be controlled by crosstalk between endothelial cells and vascular smooth muscle cells (VSMC). When vessel maturation induced by VSMCs is inhibited by introducing a soluble form of the receptor tyrosine kinase Tek, MT1-MMP distribution is no longer restricted to the endothelial tip cells, but instead distributes throughout the neovessel network in vitro as well as ex vivo. Taken together, these data demonstrate that vascular maturation coordinated by endothelial cell/mural cell interactions redirects MT1-MMP expression to the neovessel tip where the protease regulates matrix remodeling at the leading edge of the developing vasculature.

Key words: MT1-MMP, Angiogenesis, Endothelial cells, Mural cells, Type I collagen

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