FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium

Cell Death Differ. 2006 Jul;13(7):1088-96. doi: 10.1038/sj.cdd.4401803. Epub 2006 Jan 27.

Abstract

Recent evidences suggest that Abeta peptides modulate endothelial cell (EC) functions. At low concentrations, Abeta1-40 enhances the pro-angiogenic activity of FGF-2, whereas deposition of excess Abeta causes EC dysfunction and cerebral amyloid angiopathy (CAA). We investigated whether FGF-2 attenuates EC dysfunction caused by pathological Abeta levels. We studied Abeta1-40 on EC survival, as well as on signals responsible of their angiogenic phenotype. At 5-50 microM Abeta1-40 reduced EC population, caused apoptosis, downregulated FGF-2 production, inhibited FGF-2 binding to heparin, and FGFR1 phosphorylation. Toxic effects were owing to lack of FGF-2 stimulation, as EC overexpressing FGF-2 displayed extraordinary resistance to Abeta1-40 injuries. The FGF-2 mechanism responsible for reversing damages, involves the downstream enhancement of Akt, a pathway independent of eNOS activation. In conclusion, we demonstrate that FGF-2 protects EC from the effects of excess Abeta1-40, suggesting that it may attenuate the consequences of Abeta deposition in pathologies as CAA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Blotting, Western
  • CHO Cells
  • Caspase 3
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Enzyme Activation / drug effects
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism*
  • Humans
  • Mice
  • Nitric Oxide Synthase Type III / metabolism
  • Peptide Fragments / pharmacology*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Vascular Endothelial Growth Factor A
  • amyloid beta-protein (1-40)
  • Fibroblast Growth Factor 2
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases