Opposite effects of beta amyloid on endothelial cell survival: role of fibroblast growth factor-2 (FGF-2).

摘要

Amyloid beta-peptides (A ) aggregate during Alzheimer’s disease contributing to the development of the pathology. At micromolar concentration A is toxic and accumulates in neurons and in the vasculature. However, A is found at nanomolar concentrations in the plasma of healthy individuals and is also produced by endothelial cells. Here, we investigate the dual role exerted by A ?? on endothelial cell functions. Coronary vascular endothelial cells were utilized to study whether A affects endothelial cell growth and its action was compared with the effect of fibroblast growth factor-2 (FGF-2). In a range from 5 to 100 nM, A ?? concentration-dependently increased cell growth, whereas higher concentrations ofA ?? reduced cell number compared to control. At nanomolar concentration,A ?? also stimulated FGF-2mRNAexpression and protein production, which was negatively affected by micromolar concentration of the peptide. The dual role observed on endothelial cell growth, was mediated by FGF-2 biodisponibility. In fact, neutralizing anti-FGF-2 antibody inhibited A ?? -induced ERK1/2 phosphorylation at 50 nM. 5 M inhibited ERK1/2 activation over control and this was reflected by diminished cell growth which was recovered by exogenous FGF-2 administration. These results suggest that low A concentrations stimulate endothelial cells to acquire an angiogenic phenotype through interaction with endogenous FGF-2 and induction of its synthesis. In contrast, accumulation of A results toxic for endothelial cells and at these concentrations A peptide looses its ability to prime FGF-2 cycle. This may be a fundamental pathological event which might contribute to the worsening of the pathology.