Published online before print May 24, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060896

Accepted for publication March 28, 2007.

Article

Inhibition of Inflammatory Lymphangiogenesis by Integrin 5 Blockade

Tina Dietrich^*@, Jasmine Onderka^*, Felix Bock^*, Friedrich E. Kruse^*, Dörte Vossmeyer, Roland Stragies, Grit Zahn, and Claus Cursiefen^*

From the Department of Ophthalmology,* University of Erlangen-Nürnberg, Erlangen; and Jerini AG, Berlin, Germany

^@ To whom correspondence should be addressed. E-mail: tinadie{at}gmx.net.

	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 5 and v on both resting and activated lymphatic vessels in vivo. Integrin 5-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 5 and v using inhibiting molecules did not significantly increase the anti-lymphangiogenic effect in vivo, thus suggesting an important functional role of integrin 5 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.

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