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alphaB-crystallin regulation of angiogenesis by modulation of VEGF.

alphaB-crystallin is a chaperone belonging to the small heat shock protein family. Herein we show attenuation of intraocular angiogenesis in alphaB-crystallin knockout (alphaB-crystallin(-/-)) mice in 2 models of intraocular disease: oxygen-induced retinopathy and laser-induced choroidal neovascularization. Vascular endothelial growth factor A (VEGF-A) mRNA and hypoxia inducible factor-1alpha protein expression were induced during retinal angiogenesis, but VEGF-A protein expression remained low in alphaB-crystallin(-/-) retina versus wild-type mice, whereas VEGF-R2 expression was not affected. Both alphaB-crystallin and its phosphorylated serine59 formwere expressed, and immunoprecipitation revealed alphaB-crystallin binding to VEGF-A but not transforming growth factor-beta in cultured retinal pigment epithelial (RPE) cells. alphaB-crystallin and VEGF-A are colocalized in the endoplasmic reticulum in RPE cells under chemical hypoxia. alphaB-crystallin(-/-) RPE showed low VEGF-A secretion under serum-starved conditions compared with wild-type cells. VEGF-A is polyubiquitinated in control and alphaB-crystallin siRNA treated RPE; however, mono-tetra ubiquitinated VEGF-A increases with alphaB-crystallin knockdown. Endothelial cell apoptosis in newly formed vessels was greater in alphaB-crystallin(-/-) than wild-type mice. Proteasomal inhibition in alphaB-crystallin(-/-) mice partially restores VEGF-A secretion and angiogenic phenotype in choroidal neovascularization. Our studies indicate an important role for alphaB-crystallin as a chaperone for VEGF-A in angiogenesis and its potential as a therapeutic target.

Pubmed ID: 20023214

Authors

  • Kase S
  • He S
  • Sonoda S
  • Kitamura M
  • Spee C
  • Wawrousek E
  • Ryan SJ
  • Kannan R
  • Hinton DR

Journal

Blood

Publication Data

April 22, 2010

Associated Grants

  • Agency: NEI NIH HHS, Id: EY01545
  • Agency: NEI NIH HHS, Id: EY03040

Mesh Terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Choroidal Neovascularization
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Knockout
  • Retinal Pigment Epithelium
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor A
  • alpha-Crystallin B Chain