Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 208, Issue 5, Pages 1083-1092Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20092277
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Funding
- Kyoto Prefectural University
- Deutsche Forschungsgemeinschaft [Cu 47/1-1, Cu 47/1-2, SFB 643[TP B10]]
- National Institutes of Health [EY10765, EY15472, EY12963]
- Interdisciplinary Center for Clinical Research Erlangen [A9]
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Lymphangiogenesis plays an important role in tumor metastasis and transplant outcome. Here, we show that thrombospondin-1 (TSP-1), a multifunctional extracellular matrix protein and naturally occurring inhibitor of angiogenesis inhibits lymphangiogenesis in mice. Compared with wild-type mice, 6-mo-old TSP-1-deficient mice develop increased spontaneous corneal lymphangiogenesis. Similarly, in a model of inflammation-induced corneal neovascularization, young TSP-1-deficient mice develop exacerbated lymphangiogenesis, which can be reversed by topical application of recombinant human TSP-1. Such increased corneal lymphangiogenesis is also detected in mice lacking CD36, a receptor for TSP-1. In these mice, repopulation of corneal macrophages with predominantly WT mice via bone marrow reconstitution ameliorates their prolymphangiogenic phenotype. In vitro, exposure of WT macrophages to TSP-1 suppresses expression of lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and VEGF-D, but not of a primarily hemangiogenic factor VEGF-A. Inhibition of VEGF-C is not detected in the absence or blockade of CD36. These findings suggest that TSP-1, by ligating CD36 on monocytic cells, acts as an endogenous inhibitor of lymphangiogenesis.
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