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C. Cursiefen, F. Bock, J. Onderka, F. E. Kruse, K. Maruyama, J. Lawler, R. Dana, S. Masli; Thrombospondin 1 Is an Endogenous Inhibitor of Inflammatory Lymphangiogenesis and Maintains Corneal Lymphangiogenic Privilege. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3196.
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Lymphangiogenesis, i.e. the outgrowth of new from preexisting lymph vessels, is an important early step in tumor metastasis and transplant host sensitization. Whereas with VEGF A, C and D at least some endogenous lymphangiogenic growth factors have been identified, so far no endogenous inhibitor of lymphangiogenesis is known.
We tested the anti(hem)angiogenic factor thrombospondin (TSP) 1 for its antilymphangiogenic effect using the mouse model of inflammation-induced corneal neovascularization and TSP-deficient mice.
A significantly increased lymphangiogenic response was found in TSP 1-/- compared to wildtype mice. Furthermore, untreated TSP 1-/- mice displayed mild, spontaneous, isolated lymphangiogenesis. Sine TSP 1-/- mice had elevated corneal levels of the lymphangiogenic growth factor VEGF C, since monocytes are a prime source of VEGF C during inflammation and since the corneal stroma is endowed with numerous macrophages, we next examined the role of the monocytic TSP 1-receptor CD36 on inflammation induced lymphangiogenesis. CD36-/- mice displayed a significant increase in both inflammation-induced hem- and lymphangiogenesis. Since CD36 immunohistochemically was not expressed on ocular lymphatic vessels, but on resident corneal CD11b+ monocytic cells, an indirect antilymphangiogenic effect of TSP 1 via CD36-ligation on monocytes was hypothesized. Indeed, reconstitution of CD36-/- mice with wildtype bone-marrow reversed the lymphangiogenic phenotype of CD36-/- mice.
We propose TSP 1 as endogenous inhibitor of (inflammation-induced) lymphangiogenesis, and suggest its mode of action to be indirectly via ligation of CD36 on bone-marrow derived monocytic cells. TSP 1 therefore contributes both to the "anti(lymph)angiogenic" privilege as well as the "immune" privilege of the cornea.#
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