Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5

J Biol Chem. 2002 Mar 15;277(11):9492-7. doi: 10.1074/jbc.M108004200. Epub 2002 Jan 8.

Abstract

We have previously shown that intravitreal injection of plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibits ischemia-induced retinal neovascularization in a rat model. Here we report that K5 down-regulates an endogenous angiogenic stimulator, vascular endothelial growth factor (VEGF) and up-regulates an angiogenic inhibitor, pigment epithelium-derived factor (PEDF) in a dose-dependent manner in vascular cells and in the retina. The regulation of VEGF and PEDF by K5 in the retina correlates with its anti-angiogenic effect in a rat model of ischemia-induced retinopathy. Retinal RNA levels of VEGF and PEDF are also changed by K5. K5 inhibits the p42/p44 MAP kinase activation and nuclear translocation of hypoxia-inducible factor-1alpha, which may be responsible for the down-regulation of VEGF. Down-regulation of endogenous angiogenic stimulators and up-regulation of endogenous angiogenic inhibitors, thus leading toward restoration of the balance in angiogenic control, may represent a mechanism for the anti-angiogenic activity of K5.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Angiogenesis Inhibitors / pharmacology*
  • Down-Regulation
  • Endothelial Growth Factors / antagonists & inhibitors*
  • Endothelial Growth Factors / genetics
  • Eye Proteins*
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Kringles
  • Lymphokines / antagonists & inhibitors*
  • Lymphokines / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Growth Factors*
  • Phosphorylation
  • Plasminogen / pharmacology*
  • Protein Biosynthesis*
  • Proteins / genetics
  • RNA, Messenger / analysis
  • Retina / metabolism
  • Retinal Neovascularization
  • Serpins / biosynthesis*
  • Serpins / genetics
  • Transcription Factors / metabolism
  • Up-Regulation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Angiogenesis Inhibitors
  • Endothelial Growth Factors
  • Eye Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines
  • Nerve Growth Factors
  • Proteins
  • RNA, Messenger
  • Serpins
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • pigment epithelium-derived factor
  • Plasminogen
  • Mitogen-Activated Protein Kinases