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B.K. Ambati, N. Singh, P. Jani, R. Caldwell, K. Smith, M. Nozaki, B. Raisler, D. Samuelson, A. Orecchia, J. Ambati; Soluble Flt Is Essential for Corneal Avascularity: Biochemical and Comparative Anatomical Studies . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1600.
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© ARVO (1962-2015); The Authors (2016-present)
To determine if corneal avascularity is due to soluble VEGF receptor–1 (sflt–1).
Mouse and human corneas were assayed for sflt–1. Binding of VEGF to sflt–1 was assessed by immunoprecipitation. RNAi was used to ablate sflt–1 in mouse corneas in vivo, and ectopic plasmid–driven expression of siRNA–resistant sflt–1 was performed to assess restoration of avascularity. To assess effects of corneal injury on sflt–1, two models were used. Following silver nitrate cautery of mouse limbus, adjacent vascularized corneal sectors were compared to nonvascularized cornea for sflt–1. Following mechanical–alkali corneal injury sflt–1 was assessed at timepoints correlating to vascular regression.
Comparative anatomic studies of animals with physiologic corneal vascularization were performed in comparison with close phylogenetic relatives. sflt–1 in Antillean manatees, which normally have vascularized corneas, was compared versus elephants and pilot whales, which have avascular corneas. sflt–1 was assayed in corn1, nude, and Pax6+/– mice that have vascularized corneas.
sflt–1 is expressed in wild–type mouse and human corneal epithelium and stroma. It is downregulated in neovascularized human corneas. VEGF is sequestered by sflt–1 in normal cornea but much less so in neovascularized corneas. In situ ablation of sflt–1 eliminates corneal avascularity in the mouse. Corneal avascularity is restored by enforced expression of siRNA–resistant sflt–1. Silver nitrate cautery induces sectoral vascularization and suppresses sflt–1. Mechanical–alkali trauma removes corneal epithelium, the primary source of sflt–1, and induces vigorous circumferential corneal neovascularization, which regresses 4–6 weeks after injury, at which point sflt–1 is present in recovering corneal epithelium.
Antillean manatees do not express sflt–1 in contrast to elephants and pilot whales. sflt–1 is reduced or absent in corn1, nude, and Pax6+/– mice.
sflt–1 is a key mediator of corneal avascularity. Its knockdown eliminates avascularity and its restoration prevents vascularization. sflt–1 is decreased following corneal injury from silver nitrate or alkali–mechanical trauma, but corneal compensatory mechanisms lead to sflt–1 restoration and regression of corneal vessels. Comparative anatomical studies support the thesis that sflt–1 is critical to corneal avascularity
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