Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells.
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.
Yana
Ikuo
I
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
Sagara
Hiroshi
H
Takaki
Satoshi
S
Takatsu
Kiyoshi
K
Nakamura
Kenji
K
Nakao
Kazuki
K
Katsuki
Motoya
M
Taniguchi
Shun-ichiro
S
Aoki
Takanori
T
Sato
Hiroshi
H
Weiss
Stephen J
SJ
Seiki
Motoharu
M
D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000494:pharmacology; D042787:Receptor, TIE-2; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D046509:Tissue Culture Techniques; D001616:beta-Galactosidase / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; C507096:Mmp14 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; D003094:Collagen; C080985:batimastat; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D001616:beta-Galactosidase; D053511:Matrix Metalloproteinase 14