April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Endogenous VEGF-C Trapping by Angiogenic Vessels Unveils the Mystery Behind FGF-2-Induced Selective Lymphangiogenesis
Author Affiliations & Notes
  • A. Hafezi-Moghadam
    Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
  • S. Nakao
    Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
  • S. Zandi
    Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
  • Y. Hata
    Departments of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • S. Kawahara
    Departments of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • R. Arita
    Departments of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • D. Sun
    Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
  • M. I. Melhorn
    Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
  • Y. Ito
    Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
  • T. Ishibashi
    Departments of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • Footnotes
    Commercial Relationships  A. Hafezi-Moghadam, None; S. Nakao, None; S. Zandi, None; Y. Hata, None; S. Kawahara, None; R. Arita, None; D. Sun, None; M.I. Melhorn, None; Y. Ito, None; T. Ishibashi, None.
  • Footnotes
    Support  NIH grants HL086933 and AI050775, Massachusetts Lions Eye Research Fund Inc., MPOB, and Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 4752. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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).

Results: : 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.

Conclusions: : 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.

Keywords: vascular endothelial growth factor • neovascularization • microscopy: light/fluorescence/immunohistochemistry 
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