RhoA-mediated signaling in Notch-induced senescence-like growth arrest and endothelial barrier dysfunction.
RhoA-mediated signaling in Notch-induced senescence-like growth arrest and endothelial barrier dysfunction.
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DOI：
10.1161/atvbaha.110.221945
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Urs S
中科院分区：
文献类型：
--
作者：
Venkatesh D;Fredette N;Rostama B;Tang Y;Vary CP;Liaw L;Urs S
Notch signaling has a critical role in vascular development and morphogenesis. Activation of Notch in endothelial cells led to a senescence-like phenotype with loss of barrier function. Our objective was to understand the molecular pathways mediating this phenotype. Human primary endothelial cells increase expression of Notch receptors and ligands during propagation in vitro towards natural senescence. This senescence was induced at low passage with Notch activation. We characterized the pathways activated downstream of Notch signaling. Notch was activated by Dll4 ligand or constitutively active Notch receptors, and measured for cell proliferation, migration, and sprouting. Notch signaling triggered early senescence in low passage cells, characterized by increased p53 and p21 expression. The senescence phenotype was associated with hyperpermeability of the monolayer, with disrupted VE-cadherin and β-catenin levels and localization. Consistent with changes in cell shape and contact, we demonstrate that Notch activation increases myosin light chain (MLC) phosphorylation by activating Rho kinase. Inhibition of Rho abrogated Notch-induced MLC phosphorylation, and led to enhanced barrier function by reorganizing F-actin to β-catenin containing cell-cell adherens junctions. Our findings show that RhoA/Rho kinase regulation by Notch signaling in endothelial cells trigger a senescence phenotype associated with endothelial barrier dysfunction.
