In vitro effect of aspartame in angiogenesis induction.
Aspartame (APM) is the most widely used artificial sweetener and is added to a wide variety of foods, beverages, drugs, and hygiene products. In vitro and in vivo tests have reported contradictory data about APM genotoxicity. We evaluated the angiogenic effect of APM in an in vitro model using blood vessel development assay (Angio-Kit), cultured endothelial cells and fibroblasts. The release of IL-6, VEGF-A, and their soluble receptors sIL-R6 and sVEGFR-2 were determined over time in the conditioned medium of the Angio-Kit system, endothelial cells and cell lines with fibroblast properties after APM treatment. Reactive oxygen species (ROS) formation, cell viability, and stimulation of the extracellular signal-regulated kinases (erk1/2) and protein p38 were also evaluated. Exposure to APM induced blood vessel formation. ROS production was observed in endothelial cells after APM treatment, which was associated with a slight cell cytotoxicity. Neither intracellular ROS formation nor cell death was observed in fibroblasts. APM increases the levels of inflammatory mediator IL-6, VEGF and their soluble receptors released from endothelial cells into the medium. APM treatment induces VEGF-pathway activation by erk1/2 and p38 phosphorylation. APM at low doses is an angiogenic agent that induces regenerative cytokine production leading to the activation of MAPKs and resulting in the formation of new blood vessels.
Alleva
Renata
R
Department of Anesthesiology, IRCCS Orthopaedic Institute Rizzoli, Bologna, Italy. rena.alleva@gmail.com
Borghi
Battista
B
Santarelli
Lory
L
Strafella
Elisabetta
E
Carbonari
Damiano
D
Bracci
Massimo
M
Tomasetti
Marco
M
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D001218:Aspartame / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009994:Osmolar Concentration; D017382:Reactive Oxygen Species; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012995:Solubility; D013549:Sweetening Agents / Q000494:pharmacology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D019947:Receptors, Interleukin-6; D013549:Sweetening Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D001218:Aspartame