title: Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany. ccursiefen@yahoo.com
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Maruyama
authors.forename: Felix
authors.initials: F
authors.lastname: Bock
authors.forename: Daniel
authors.initials: D
authors.lastname: Saban
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sadrai
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
authors.forename: Sharmila
authors.initials: S
authors.lastname: Masli
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003315:Cornea / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016510:Corneal Neovascularization / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019700:Thrombospondin 1 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D019700:Thrombospondin 1; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse