Inhibition of inflammatory lymphangiogenesis by integrin α5 blockade

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. Immunobistochemistry revealed novel expression of both integrin alpha 5 and alpha v on both resting and activated lymphatic vessels in vivo. Integrin alpha 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 a5 and av using inhibiting molecules did not significantly increase the anti-lymphangiogenic effect in vivo, thus suggesting an important functional role of integrin a5 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.