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A. Hafezi-Moghadam, S. Nakao, S. Zandi, Y. Hata, S. Kawahara, R. Arita, D. Sun, M. I. Melhorn, Y. Ito, T. Ishibashi; Endogenous VEGF-C Trapping by Angiogenic Vessels Unveils the Mystery Behind FGF-2-Induced Selective Lymphangiogenesis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4752.
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Fibroblast growth factor 2 (FGF-2) induces both angiogenesis and lymphangiogenesis. Low doses of FGF-2 induce selective lymphangiogenesis, providing the first evidence that lymphatic growth is possible without angiogenesis, however, the underlying mechanisms are not understood.
FGF-2 was implanted in mouse cornea using the micropocket assay. Immunostaining of LYVE-1 and CD31 was performed to quantify angiogenesis and lymphangiogenesis. To examine VEGF-C and VEGFR-2 (R2) regulation, GF-implanted corneas were harvested and samples were examined using western blotting. In vivo molecular imaging in corneal angiogenic vessels was performed using anti-R2 mAb- or IgG-conjugated microspheres (MS).
In vivo molecular imaging revealed increased VEGFR-2 expression in FGF-2-induced angiogenic tips (n=6, P<0.01), areas in which lymphatic growth is most impeded. FGF-2 implantation (100ng) significantly increased VEGFR-2 expression in angiogenic vessels, indicating the existence of an endothelial trapping mechanism for VEGF-C (n=6, P<0.01). In contrast, FGF-2 (12.5ng) at concentrations that selectively causes lymphatic growth did not affect endothelial VEGFR-2 expression (n=6), allowing VEGF-C to reach pre-existing lymphatics.
VEGFR-2-upregulation, in angiogenic endothelium, traps VEGF-C and reduces its concentration in the extracellular matrix, therewith impeding lymphangiogenesis. Absence of the endothelial trapping mechanism permits selective lymphatic growth, for instance with low FGF-2 concentrations. Growth factor clearance by receptor-mediated internalization is a new paradigm explaining various characteristics of lymphatics.
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