Inflammation dysregulates Notch signaling in endothelial cells: implication of Notch2 and Notch4 to endothelial dysfunction

Abstract

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.