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J.Z. Baffi, M. Nozaki, J. Witta, B.J. Raisler, S. De Falco, M. Shibuya, B.K. Ambati, J. Ambati; PLGF–1 Induces Corneal Neovascularization by Silencing Soluble VEGFR–1 . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4494.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To determine the role of soluble vascular endothelial growth factor receptor–1 (sVEGFR–1) in maintaining avascularity of the cornea by testing the angiogenic response to placenta growth factor–1 (PlGF–1), a VEGFR–1 specific ligand. Methods: Expression of VEGF–A, VEGF–B, PlGF–2, VEGFR–1, and sVEGFR–1 was determined in C57BL/6J and Balb/C mice by western blotting, immunohistochemistry, or in situ hybridization. The angiogenic response of C57BL/6J, Balb/C, and Vegfr–1 tyrosine kinase–/– mice to intrastromal delivery of plasmids coding for human PlGF–1 or for D72A/E73A–PlGF–1, a mutant form that does not bind or activate VEGFR–1 was assessed by photographic and flatmount examination of CD31 and LYVE–1 expression. Results: Although VEGF–A is present in the cornea it remains avascular. Most of the VEGFR–1 protein in the cornea was of the soluble form. sVEGFR–1 mRNA was present in greater quantities in the epithelium than in the stroma. Greater amounts of sVEGFR–1 protein were present in the cornea of C57BL/6J compared to Balb/C mice. VEGF–B and PlGF–2 were not detected in the cornea. PlGF–1 plasmid induced corneal neovascularization in C57BL/6J and Vegfr–1 tyrosine kinase–/– mice within 14 days and in Balb/C mice within 7 days. D72A/E73A–PlGF–1 did not induce neovascularization at these time points. Conclusions: Collectively these findings demonstrate that PlGF–1 induces corneal neovascularization by unsequestering VEGF–A from sVEGFR–1, and not via direct signaling through VEGFR–1 or indirect signaling via VEGFR–2 through VEGF–A heterodimerization. Silencing sVEGFR–1 activity abolishes corneal avascularity, highlighting its importance in maintaining vascular apartheid between the cornea and conjunctiva.
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