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R. Albuquerque, B. Raisler, M. Nozaki, J.Z. Baffi, A. Takeda, J.M. Collinson, L.J. Leiper, S. Ikeda, B.K. Ambati, J. Ambati; Corneal Avascularity Is Due to Soluble VEGF Receptor–1 . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1628.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal avascularity, which is required for optical clarity and optimal vision, is still an active subject of mechanistic inquiry. We hypothesized that the cornea remains avascular despite the presence of vascular endothelial growth factor (VEGF)–A due to expression of soluble VEGFR–1 (sVEGFR–1), an endogenous VEGF–A trap.
VEGF–A and sVEGFR–1 expression were assayed by ELISA, western blotting, immunostaining, and in situ hybridization in vascularized corneas of corn1 and Pax6 +/– mice, and manatees (which have spontaneously vascularized corneas) and in background matched control mice and elephants. Corneal vascularization was assessed by CD31–stained flat mounts. Neutralizing or non–neutralizing antibodies against VEGFR–1 were injected subconjunctivally.
We found that corn1 and Pax6 +/– mice, and manatees do not express sVEGFR–1 in the cornea, whereas normal mice, elephants (the closest extant phylogenetic manatee relatives), express abundant sVEGFR–1. In wild type or Vegfr1 tk –/– mice, neutralizing VEGFR–1 antibody, but not non–neutralizing antibody, induced corneal neovascularization and increased free VEGF–A. As previously reported, in vivo suppression of sVEGFR–1 by protein blockade, RNA interference, or conditional gene disruption all abolished corneal avascularity in mice.
VEGF–A in the cornea is normally bound in an inactive form by sVEGFR–1, maintaining an avascular cornea. In animals with corneal vascularity, sVEGFR–1 is absent or substantially reduced subsequently freeing VEGF–A and driving angiogenesis. Soluble VEGFR–1 is the dominant anti–angiogenic factor preserving the vascular apartheid between the cornea and the conjunctiva. This knowledge can serve to rationally guide usage of the avascular cornea as a platform for studies on angiogenesis, providing insights into the relative immunologic privilege enjoyed by this tissue, and supporting sVEGFR–1 use in the treating blinding corneal diseases.
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