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E-mail contact: herlynm@wistar.org
The requirement for Notch signaling in vasculogenesis and angiogenesis is well documented. In a previous study, we showed that activation of the Notch pathway in endothelial cells induces differentiation-associated growth arrest; however, the underlying mechanism remains to be elucidated. Here, we show that activation of the Notch pathway by either stimulation of cell surface Notch receptors with crosslinked soluble Delta-like 4 (sDll4)/Jagged1 (sJag1) or constitutive expression of the Notch1 intracellular domain (NIC) suppresses endothelial cell proliferation. This suppression is mediated by the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Following Notch1 activation, both pathways were suppressed in endothelial cells, and alterations in MAPK or PI3K/Akt pathway activity reversed Notch1-induced growth inhibition. Furthermore, we found the effect of Notch1 on endothelial cells to require Mastermind-like (MAML). Overexpression of a dominant-negative mutant of MAML1 antagonized the effects of activated Notch1 on the MAPK and PI3K/Akt pathways. Ectopic expression of Hairy/Enhancer of Split 1 (HES1) consistently reproduced the inhibitory effect of NIC on endothelial cell proliferation. Together, our data demonstrate that the Notch/MAML-HES signaling cascade can regulate both MAPK and PI3K/Akt pathways, which suggests a molecular mechanism for the inhibitory effect of Notch signaling on endothelial cell proliferation.--Liu Z.-J., Xiao M., Balint K., Soma A., Pinnix C. C., Capobianco A. J., Velazquez O. C., Herlyn M. Inhibition of endothelial cell proliferation by Notch1 signaling is medicated by repressing MAPK and PI3K/Akt pathways and rquires MAML1.
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