Opposite effects of beta amyloid on endothelial cell survival: role of fibroblast growth factor-2 (FGF-2).
Amyloid beta-peptides (Abeta) aggregate during Alzheimer's disease contributing to the development of the pathology. At micromolar concentration Abeta is toxic and accumulates in neurons and in the vasculature. However, Abeta 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 Abeta(1-40) on endothelial cell functions. Coronary vascular endothelial cells were utilized to study whether Abeta 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, Abeta(1-40) concentration-dependently increased cell growth, whereas higher concentrations of Abeta(1-40) reduced cell number compared to control. At nanomolar concentration of the peptide Abeta(1-40) also stimulated FGF-2mRNA expression 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 Abeta(1-40)-induced ERK1/2 phosphorylation at 50 nM. 5 muM 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 Abeta concentrations stimulate endothelial cells to acquire an angiogenic phenotype through interaction with endogenous FGF-2 and induction of its synthesis. In contrast, accumulation of Abeta results toxic for endothelial cells and at these concentrations Abeta 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.
Cantara
Silvia
S
Department of Molecular Biology, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
Ziche
Marina
M
Donnini
Sandra
S
D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); D016222:Fibroblast Growth Factor 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3