Deletion of HIF-1α partially rescues the abnormal hyaloid vascular system in Cited2 conditional knockout mouse eyes

Mol Vis. 2012;18:1260-70. Epub 2012 May 11.

Abstract

Purpose: Cited2 (CBP/p300-interacting transactivators with glutamic acid (E) and aspartic acid (D)-rich tail 2) is a member of a new family of transcriptional modulators. Cited2 null embryos exhibit hyaloid hypercellularity consisting of aberrant vasculature in the eye. The purpose of the study is to address whether abnormal lenticular development is a primary defect of Cited2 deletion and whether deletion of hypoxia inducible factor (HIF)-1α or an HIF-1α target gene, vascular endothelial growth factor (VEGF), could rescue abnormal hyaloid vascular system (HVS) in Cited2 deficient adult eyes.

Methods: Le-Cre specific Cited2 knockout (Cited2(CKO)) mice with or without deletion of HIF-1α or VEGF were generated by standard Cre-Lox methods. Eyes collected from six-eight weeks old mice were characterized by Real Time PCR and immunohistological staining.

Results: Cited2(CKO) mice had smaller lenses, abnormal lens stalk formation, and failed regression of the HVS in the adult eye. The eye phenotype had features similar to persistent hyperplastic primary vitreous (PHPV), a human congenital eye disorder leading to abnormal lenticular development. Deletion of HIF-1α or VEGF in Cited2 knockout eyes partially rescued the abnormal HVS but had no effect on the smaller lens and abnormal lens stalk differentiation. Intravitreal injection of Topotecan (TPT), a compound that inhibits HIF-1α expression, partially eliminated HVS defects in Cited2(CKO) lenses.

Conclusions: Abnormal HVS is a primary defect in Cited2 knockout mice, resulting in part from dysregulated functions of HIF-1 and VEGF. The Cited2(CKO) mouse line could be used as a novel disease model for PHPV and as an in vivo model for testing potential HIF-1 inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Disease Models, Animal
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / deficiency
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Lens, Crystalline / drug effects
  • Lens, Crystalline / metabolism*
  • Lens, Crystalline / pathology
  • Mice
  • Mice, Knockout
  • Persistent Hyperplastic Primary Vitreous / genetics
  • Persistent Hyperplastic Primary Vitreous / metabolism
  • Persistent Hyperplastic Primary Vitreous / pathology
  • Protein Binding
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics*
  • Sequence Deletion
  • Topoisomerase I Inhibitors / administration & dosage
  • Topotecan / administration & dosage
  • Trans-Activators / deficiency
  • Trans-Activators / genetics*
  • Vascular Endothelial Growth Factor A / deficiency
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • Cited2 protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • Topoisomerase I Inhibitors
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • Topotecan