title: Inhibition of inflammatory lymphangiogenesis by integrin alpha5 blockade.
abstract: The interaction between endothelial cells and extracellular matrix proteins plays an important role in (hem)angiogenesis. Integrins are able to mediate the outgrowth of newly formed blood vessels. In contrast, the role of integrins in lymphangiogenesis, ie, the outgrowth of new from pre-existing lymphatic vessels, has so far been unclear. Here, expression and functional relevance of integrins on lymphatic endothelium in vivo was investigated using the mouse model of combined inflammatory corneal hemangiogenesis and lymphangiogenesis. Immunohistochemistry revealed novel expression of both integrin alpha5 and alphav on both resting and activated lymphatic vessels in vivo. Integrin alpha5-inhibiting small molecules significantly blocked the outgrowth of new lymphatic vessels into the cornea in a dose-dependent manner. The outgrowth of blood vessels was less significantly affected by this treatment, thus allowing for selective inhibition of lymphangiogenesis at lower dosages. Combined inhibition of integrin alpha5 and alphav using inhibiting molecules did not significantly increase the anti-lymphangiogenic effect in vivo, thus suggesting an important functional role of integrin alpha5 in lymphangiogenesis. In summary, our findings demonstrate novel expression of specific integrins on growing lymphatic endothelial cells in vivo and reveal their functional role during lymphangiogenesis. This opens new treatment options for selective inhibition of lymphangiogenesis, eg, in oncology and transplant immunology.
authors.affiliation: Department of Ophthalmology, University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen, Germany. tinadie@gmx.net
authors.forename: Tina
authors.initials: T
authors.lastname: Dietrich
authors.forename: Jasmine
authors.initials: J
authors.lastname: Onderka
authors.forename: Felix
authors.initials: F
authors.lastname: Bock
authors.forename: Friedrich E
authors.initials: FE
authors.lastname: Kruse
authors.forename: Dörte
authors.initials: D
authors.lastname: Vossmeyer
authors.forename: Roland
authors.initials: R
authors.lastname: Stragies
authors.forename: Grit
authors.initials: G
authors.lastname: Zahn
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
mesh_terms: D000818:Animals; D003315:Cornea / Q000098:blood supply; D004728:Endothelium, Corneal; D004730:Endothelium, Vascular; D066298:In Vitro Techniques; D007249:Inflammation / Q000150:complications; D039482:Integrin alpha5 / Q000378:metabolism* / Q000502:physiology; D039564:Integrin alphaV / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects*; D042601:Lymphatic Vessels / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D039482:Integrin alpha5; D039564:Integrin alphaV; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3