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J. Z. Baffi, M. Nozaki, A. Takeda, M. Kleinman, K. Yamada, B. J. Raisler, S. de Falco, B. K. Ambati, J. Ambati; Suppression of Choroidal Neovascularization in PlGF -/- Mice Is Due to Elevated VEGF-A and VEGFR-1 Activation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):6012.
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Gene ablation of PlGF, a VEGFR-1 ligand, has been shown to inhibit experimental choroidal neovascularization (CNV). However, we have shown that VEGFR-1 activation by elevated VEGF-A levels suppresses CNV while intraocular VEGFR-1 neutralization augments CNV. To reconcile these findings we studied the role of VEGF-A and VEGFR-1 in PlGF-/- mice.
VEGF-A levels were measured in PlGF-/- and wild-type mice by ELISA. CNV was induced by laser injury and volumes measured 7 days later by confocal evaluation of Isolectin B4 staining of RPE-choroid flatmounts. Neutralizing antibodies (Ab) against VEGF-A or VEGFR-1, or control IgG were injected into the vitreous following injury.
VEGF-A levels in the RPE/choroid of PlGF-/- mice were nearly 4.7 times that of wild-type mice. CNV volume was reduced by 60% in PlGF-/- mice compared to wild-type mice. VEGF-A and VEGFR-1 Abs, but not control IgG, eliminated this suppression of CNV in PlGF-/- mice and restored CNV size to wild-type levels.
These findings clarify the complex role of VEGFR-1 in CNV and highlight its principal role as an anti-angiogenic molecule in this system. Further they extend our previous demonstration that excess VEGF-A levels, which in PlGF-/- mice are likely due to absence of the PlGF/VEGF-A heterodimers, can suppress experimental CNV.
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