Blockade of VEGFR3-signalling specifically inhibits lymphangiogenesis in inflammatory corneal neovascularisation |
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Authors: | Felix Bock Jasmine Onderka Tina Dietrich Björn Bachmann Bronislaw Pytowski Claus Cursiefen |
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Institution: | (1) Department of Ophthalmology, University of Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany;(2) ImClone Systems Inc., New York, NY, USA |
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Abstract: | Purpose Inflammatory corneal hem- and lymphangiogenesis occurring both prior to as well as after penetrating keratoplasty significantly
increase the risk for subsequent immune rejections. The purpose of this study was to analyze whether the blocking anti-VEGFR3
antibody mF4-31C1 is able to inhibit the outgrowth of pathologic new lymphatic vessels in a mouse model of suture-induced,
inflammatory corneal neovascularisation, and whether this antibody specifically inhibits lymphangiogenesis without affecting
hemangiogenesis.
Methods Three interrupted 11-0 nylon sutures were placed into the corneal stroma of BALB/c mice (6 weeks old) and left in place for
7 days to induce neovascularisation. The treatment group (n = 9) received the anti-VEGFR3 antibody mF4-31C1 intraperitoneally on the day of surgery and 3 days later (0.5 mg/mouse).
Control mice received an equal amount of control IgG solution. For immunohistochemistry, corneal flat mounts were stained
with LYVE-1 as a specific lymphatic vascular endothelial marker and with CD31 as panendothelial marker. Morphometry was performed
with the image analysis software analySIS^B (Soft Imaging Systems GmbH, Münster, Germany). To improve the objectivity and
precision of the morphometrical analysis, we established a modified method using grey filter sampling on monochromatic pictures.
Results The mF4-31C1 antibody-treated mice displayed nearly complete inhibition of lymphangiogenesis compared with IgG controls (p < 0.006). In contrast, there was no significant inhibitory effect observed with respect to blood vessel growth (p > 0.05).
Conclusions Inflammatory corneal lymphangiogenesis seems to depend on VEGFR3-signalling. By blocking this receptor the ingrowths of lymphatic
vessels can be inhibited almost completely, and specifically without affecting hemangiogenesis. This may open new treatment
options to promote (corneal) graft survival without affecting hemangiogenesis.
Interdisciplinary Centre for Clinical Research (IZKF) Erlangen (A9), ELAN Funds Erlangen, DFG (Cu 47/2-1). |
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Keywords: | Cornea Lymphangiogenesis VEGFR3 VEGF-C VEGF-D Inflammatory neovascularisation |
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