Inflammation Dysregulates Notch Signaling In Endothelial Cells: Implication Of Notch2 And Notch4 To Endothelial Dysfunction

INSERM, U643, Nantes F44000, France.
Biochemical pharmacology (Impact Factor: 5.01). 12/2010; 80(12):2032-41. DOI: 10.1016/j.bcp.2010.07.010
Source: PubMed


Although the involvement of the Notch pathway in several areas of vascular biology is now clearly established, its role in vascular inflammation at the endothelial level remains to be elucidated. In this study, we demonstrated that pro-inflammatory cytokines drive a specific regulation of the Notch pathway in vascular endothelial cells (ECs). In arterial ECs, TNFα strongly modulates the pattern of Notch expression by decreasing Notch4 expression while increasing Notch2 expression. Changes in Notch expression were associated with a reduction in hes1 and hey2 expression and in CBF1 reporter gene activity, suggesting that TNFα regulates both Notch expression and activity. Notch2 and Notch4 regulations occurred independently and were found to be mostly mediated by the NFκB signaling pathways and PI3-kinase signaling pathways, respectively. Functionally, TNF-mediated Notch regulation promotes caspase-dependent EC apoptosis. Finally, our findings confirmed that dysregulated Notch signaling also occurs upon inflammation in vivo and correlates with caspase activation and apoptosis. In conclusion, inflammatory cytokines elicit a switch in Notch expression characterized by Notch2 predominance over Notch4 leading to a reduced Notch activity and promoting apoptosis. Thus, here we provide evidence for a role of soluble mediators of inflammation (i.e. cytokines) in the regulation of Notch signaling and for the implication of a dysregulated Notch pathway to endothelial and vascular dysfunction.

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Available from: Béatrice Charreau
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    • "A large number of studies have shown Notch involvement in endothelial cell activation, apoptosis and proliferation. While the effects of various mediators of cell growth or cell activation on Notch pathway in endothelial cells have been well characterized [36] [37], less is known on how estrogens affect Notch in the endothelium. "
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    • "TNFα-mediated Notch inhibition is associated with endothelial cells apoptosis, as shown by caspase 3 activation in endothelial cells of lung sections from rats treated with TNFα. [45]. Since overexpression of Notch2 in endothelial cells decreases the levels of survivin, a key antiapoptotic factor, it has been suggested that TNFα signaling sensitizes endothelial cells to apoptosis by activating Notch2 and thus decreasing Notch activity [46]. "
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