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M. Leszczuk, I. Semkova, X. Shi, Y. Liang, N. Kociok, A. M. Joussen; Tumor Necrosis Factor -Alpha Receptor P75 Is Required in the Development of Choroidal Neoascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5164. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Tumor necrosis factor alpha (TNF-a), a proinflammatory cytokine is highly expressed in fibrovascular membranes isolated from AMD patients and is known to modulate choroidal neovascularization (CNV). Little is known about the role of TNF-a receptors (TNFRp55 and TNFRp75) in angiogenic signaling in vivo. TNFRp75 signaling involves activation of TNFRp75-specific kinase Bmx/Etk that has been implicated in endothelial cell migration and tube formation in vitro. Furthermore, activation of nuclear factor-kappaB in endothelial cells (ECs) via TNFRp75 stimulates the expression of antiapoptotic genes and increases ECs survival. In contrast, activation of TNFRp55 caused inhibition of ECs migration and ECs apoptosis. We investigated the role of both receptors in a mice model of CNV induced by laser-photocoagulation.
Four separate laser burns were applied to induce ruptures of Bruch's membrane and subsequent choroidal neovascularization in TNFRp55-/- and TNFRp75-/- as well as WT mice. CNV formation was compared with respect to fluorescein angiographic leakage and also by histological appearance on paraffin eye sections. Additionally, CNV lesions were assessed on choroidal flatmounts after CD31-labeling and after perfusion with rhodamine-conjugated concanavalin-A.
Pathological vascular leakage investigated by fluorescein angiography was decreased by almost 50% in TNFRp75-/- compared to WT mice, but no difference between TNFRp55-/- and WT mice was observed. Furthermore, on choroidal flat-preparations the number of the laser scars, as well as, their size and fluorescence intensity was reduced in TNFRp75-/- but not in TNFRp55-/- mice in comparison to WT animals. Histological evaluation of H&E-stained paraffin cross sections showed fibrovascular lesions in subretinal space that were larger and more severe in WT in comparison to TNFRp75-/- mice.
These results demonstrate that TNFRp55 and TNFRp75 play probably differential roles in CNV formation after laser photocoagulation. This might be due to their opposite effects on endothelial cell survival.
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