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Soluble vascular endothelial growth factor receptor-1 contributes to the corneal anti-angiogenic barrier
  1. Balamurali K. Ambati (bambati{at}mail.mcg.edu),
  2. Emory Patterson,
  3. Pooja Jani,
  4. Crystal Jenkins,
  5. Eric Higgins,
  6. Nirbhai Singh,
  7. Tushar Suthar,
  8. Nehali Vira,
  9. Kimberly Smith,
  10. Ruth Caldwell
  1. Medical College of Georgia, United States
  2. Medical College of Georgia, United States
  3. Medical College of Georgia, United States
  4. Medical College of Georgia, United States
  5. Medical College of Georgia, United States
  6. Medical College of Georgia, United States
  7. Medical College of Georgia, United States
  8. Medical College of Georgia, United States
  9. Medical College of Georgia, United States
  10. Medical College of Georgia, United States

    Abstract

    Purpose: Pathological neovascularization within the normally avascular cornea is a serious event that can interfere with normal vision. Upregulation of vascular endothelial growth factor (VEGF) has been associated with neovascularization in the eye, suggesting that maintaining low levels of VEGF is important for corneal avascularity and intact vision. This study aims to determine the expression profile and possible contribution of sVEGFR-1 to the corneal avascular barrier.

    Design: Experimental case series investigating VEGF and sFlt levels in normal and neovascularized human corneas.

    Participants: Four normal human corneas, five human corneas with alkali burns, three human corneas with aniridia, one with ocular cicatricial pemphigoid and two with interstitial keratitis were examined.

    Methods: Western Blot analysis and immunohistochemistry were performed to determine sFlt and VEGF levels in normal and neovascularized human corneas. Immunoprecipitation was utilized to demonstrate sFlt-VEGF binding.

    Results: Normal human corneas strongly express sFlt in the corneal epithelium and weakly in the corneal stroma close to the limbus. VEGF is bound by sFlt in the normal human cornea. Neovascularized human corneas have greatly reduced expression of sFlt and significantly less VEGF bound by sFlt.

    Conclusions: sFlt is highly expressed in the human cornea and normally sequesters VEGF.

    • VEGF
    • angiogenesis
    • avascularity
    • cornea
    • sflt

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    • erratum 91/4/505

      Text of Erratum
      Figure 4 & 8 were erroneous submissions; the correct figures are now presented. Lane 1 and the marker lane of Figure 8 duplicate those of Figure 4. This resulted from the fact that, during the editing process, we were asked to provide 2 separate figures demonstrating, firstly, that sFlt binds VEGF in normal human cornea (Figure 4), and secondly, that in neovascularized specimens, binding of sFlt to VEGF is reduced relative to normal (Figure 8). This does not alter the conclusions that sFlt binds VEGF and that there is reduced binding in the disease state. Also, the molecular weight in Fig. 8 in the original paper was mislabeled as 25kD rather than 46 kD. Although the gel was run under reducing conditions, for reasons unclear to the angiogenesis field, the migration of VEGF species extracted from tissues, even under reducing conditions, is known to be anomalous as it often migrates around 46 kD, suggesting a secondary/tertiary structure of the VEGF dimer that is resistant to complete reduction as noted by other investigators1-3.

      Figure 5 erroneously duplicated bands in Figure 3. We now show the correct Western blots demonstrating reduced/absent sFlt in neovascularized human corneas compared to normal corneas; these data are from experiments performed prior to the earlier incorrectly presented data.

      It should also be noted that the original Fig. 7B is a reproduction of Fig. 4d in an earlier paper of ours (Ambati et al. Nature 2006;443:993–7), which was Ref. 4 in our paper. In this paper, we showed it as an example of reduced sFlt expression in a condition associated with corneal neovascularization in humans. In the earlier paper we showed it as an example of Pax6 mutations in aniridia being associated with decreased sFlt in humans. We now show several other examples of aniridic human corneas with low levels of sFlt expression, reinforcing our conclusion that aniridic corneal neovascularization is associated with low sFlt levels. Nonetheless, the published guidelines of both Nature and BJO accord with reuse of an earlier figure.

      We regret the oversights that led to these errors of assembly and editing. Although these mistakes do not alter the conclusions of the article, we wish to inform other scientists of these problems and provide an accurate representation of our work.

      1. Kallapur SG, Bachurski CJ, Le Cras TD, et al. Vascular changes after intra-amniotic endotoxin in preterm lamb lungs. Am J Physiol Lung Cell Mol Physiol. 287: L1178-85 (2004)
      2. Tee MK & Jaffe RB. A precursor form of VEGF arises by initiation from an upstream in-frame CUG codon. Biochem J. 359: 219-226 (2001)
      3. Jingjing L, Srinivasan B, Bian X et al. VEGF is increased following coronary artery occlusion in the dog heart. Mol Cell Biochem. 214: 23-30 (2000)

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