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Activation of Notch1 Signaling in Fibroblasts Inhibits Interlukin (IL)-6 Production Whereby Proliferation, Migration and Support of Vascular Tube Formation Are Regulated

Zhao-Jun Liu.
University of Miami, Miami, Fla.

OBJECTIVES: Resent studies indicate that cytokines such as IL-6 contribute to the formation of aortic aneurysms and aneurysm rupture. Notch signaling is essential for embryonic development of the aorta, but it is unknown if alterations in postnatal Notch signaling have any roles in IL-6 production or aortic disease/treatment. We aim to investigate the role of Notch1 signaling in human fibroblasts (FB) and its effect on angiogenesis as it relates to specific effects on IL-6 secretion and basic cellular processes (proliferation, migration and vascular tube/network formation).

METHODS: The status of Notch signaling in FB was analyzed by real-time qPCR to examine gene expression of Notch receptors, ligands and target genes (Hes and Hey). FB were transduced with NIC/lentivirus (activated Notch1) and lacZ/lentivirus (control). Transduced FB were tested for proliferation by MTT and migration by scratch assays. The effects of Notch1 activation on regulating the secretion of soluble factors by FB were examined using ProteinArray analysis (18 factors were tested). The role of Notch1 activation in the ability of FB to regulate vascular tube/network formation was analyzed in a three-dimensional (3D) angiogenesis model. The role of soluble factors in mediating the effects of FB on tube/network formation was assessed, in this 3D model, by factor replacement studies. Data was analyzed by ANOVA based on results of 3 independent experiments.

RESULTS: Cultured FB express low levels of Notch receptors and ligands. Notch target genes are not induced. Upon Notch1 activation, FB proliferation and migration are inhibited and FB-supported vascular tube/network formation is also inhibited. The inhibitory effect appear to be mediated by IL-6 as ProteinArray assays demonstrated that production of IL-6 in Notch1-activated FB is significantly down-regulated and that replacement of IL-6 is able to rescue the vascular tube/network formation.

CONCLUSIONS: To our knowledge, this is the first report of Notch signaling regulating IL-6 production by fibroblasts and altering fibroblast proliferation, migration, and support of vascular tube/network formation. These novel in vitro findings in human cells carry relevance to aortic aneurismal disease and angiogenesis/vasculogenesis and will need further in vivo study in disease models.

AUTHOR DISCLOSURES: Z. Liu, None.