FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium.
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.
Donnini
S
S
Department of Molecular Biology, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
Cantara
S
S
Morbidelli
L
L
Giachetti
A
A
Ziche
M
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C078592:amyloid beta-protein (1-40); D016222:Fibroblast Growth Factor 2; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases