Herbimycin A inhibits angiogenic activity in endothelial cells and reduces neovascularization in a rat model of retinopathy of prematurity

  • McCollum G
  • Rajaratnam V
  • Bullard L
 et al. 
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Abstract

The pathogenesis of retinopathy of prematurity involves dysregulated angiogenesis resulting in pre-retinal growth of new vessels. Inhibition of tyrosine kinase-dependent pro-angiogenic signals may provide a rational therapeutic approach to the reduction of pre-retinal neovascularization. Vascular endothelial growth factor stimulates endothelial cell mitogenesis, differentiation and migration, by binding and activating the receptor tyrosine kinases vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2. One of the vascular endothelial growth factor receptor substrates implicated in vascular endothelial growth factor signal transduction is c-Src. The ability of herbimycin A, a c-Src-selective tyrosine kinase inhibitor, to inhibit vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and tube formation was investigated. The ability of the compound to inhibit pathologic angiogenesis was tested in a rat model of retinopathy of prematurity. Exposure of neonatal rats to oxygen concentrations cycling between 10 and 50% induced severe pre-retinal neovascularization in all rats. Some of the eyes of these variable oxygen-exposed rats were herbimycin A-injected or vehicle-injected 1 or 3 days post-oxygen exposure while some eyes were non-injected. All rats were sacrificed for assessment 6 days post-exposure. Herbimycin A inhibited both vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and capillary tube formation in a dose-dependent manner. Injection of herbimycin A into oxygen-treated rats 1day post-oxygen exposure produced a 63% decrease in pre-retinal neovascularization relative to vehicle (P=0·0029). There was a 41% decrease in pre-retinal neovascularization in herbimycin-injected eyes relative to vehicle-injected eyes 3 days post-oxygen (P=0·031). Pre-retinal neovascularization was reduced in vehicle-injected eyes relative to non-injected eyes at both injection times. There were no significant differences in retinal vascular area between any of the experimental groups. Based on the results of this study, herbimycin A inhibits endothelial cell proliferation and tube formation at non-toxic concentrations and reduces pre-retinal neovascularization in a rat model of retinopathy of prematurity. Reduction of angiogenesis by the inhibition of tyrosine kinase activity may be a viable route to the development of effective chemotherapies applicable to eye disease. © 2004 Elsevier Ltd. All rights reserved.

Author-supplied keywords

  • Angiogenensis
  • Herbimycin A
  • Retinal hypoxia
  • Retinopathy of prematurity
  • Tyrosine kinase
  • Vascular endothelial growth factor
  • Vasculogenesis

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Authors

  • Gary W. McCollum

  • Veera S. Rajaratnam

  • Lawrence E. Bullard

  • Rong Yang

  • John S. Penn

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