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T. Dietrich, J. Onderka, F. Bock, G. Zahn, R. Stragies, F.E. Kruse, C. Cursiefen; Inhibition Of Inflammatory Lymphangiogenesis In The Cornea By Blocking Integrin Alpha 5 . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3907.
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© ARVO (1962-2015); The Authors (2016-present)
Neovascularization of the cornea is the main cause of graft failure after corneal transplantation and the main sight–threatening complication of limbal stem cell deficiency. An up–regulation of integrins (e.g. alpha 5) on outgrowing blood vessels has previously been described. The purpose of this study was to investigate whether integrins are expressed on outgrowing lymphatic endothelium and if so whether it is possible to inhibit lymphangiogenesis by blocking a specific integrin.
Inflammatory corneal neovascularization was induced by placing three 11–0 nylon sutures in 6 week old BalbC mice in a standardized fashion. Mice in the treatment group received integrin alpha 5 inhibiting molecules systemically via subcutaneous osmotic pumps (Alzet® Pumps) for 14 days (n = 8). In the control group, only the vehicle solution was applied in the same manner (n = 9). Mice were sacrificed afterwards and whole mount preparations of the corneas were performed. For immunohistochemistry, we used LYVE–1 antibody as a specific lymphatic vascular marker and CD–31 as a panendothelial marker. The fluorescence microscopic pictures were analyzed morphometrically on digitized whole mounts using analySIS^B® software. Indirect immunohistochemistry and immunogold labeling were used to identify integrins on pathologic corneal lymphatic vessels.
By immunohistochemistry and electron microscopy, we were able to identify alpha 5 integrin expression on the endothelium of corneal lymphatic vessels. Systemic inhibition of alpha 5 integrin function by small molecules resulted in a statistically significant reduction of lymphatic vessel outgrowth from the limbus compared to the control group (p < 0.0001); inhibition of hemangiogenesis was less effective but still significant (p = 0.02). Mean inhibition of lymphangiogenesis was measured by 51 % (hemangiogenesis by 17 %, respectively).
Integrins seem to play a functional and important role in mediating lymphangiogenesis. We were able to show, that integrin alpha 5 is localized on lymphatic endothelium of vascularized mouse corneas. By inhibition of integrin alpha 5 function inflammatory lymphangiogenesis in the cornea can be inhibited. Integrin antagonists may be used to promote corneal graft survival and inhibit tumor metastasis by blocking lymphangiogenesis. Furthermore, the relatively specific inhibition of lymphangiogenesis may represent a uniquely useful tool to improve graft survival in vascularized extraocular sites.
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