Constitutively active Notch1 signaling promotes endothelial‑mesenchymal transition in a conditional transgenic mouse model

Liu,Ju; Dong,Fengyun; Jeong,James; Masuda,Takahiro; Lobe,Corrinne G.

doi:10.3892/ijmm.2014.1818

Constitutively active Notch1 signaling promotes endothelial‑mesenchymal transition in a conditional transgenic mouse model

Authors:
- Ju Liu
- Fengyun Dong
- James Jeong
- Takahiro Masuda
- Corrinne G. Lobe
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Affiliations: Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, P.R. China, Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, Toronto, Ontario, Canada
Published online on: June 24, 2014 https://doi.org/10.3892/ijmm.2014.1818
Pages: 669-676
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Endothelial-mesenchymal transition (EndoMT) is a process in which endothelial cells lose their cell-type‑specific characteristics and gain a mesenchymal cell phenotype. The Notch signaling pathway is crucial in the regulation of EndoMT; however, its roles have not been fully studied in vivo. In a previous study, we reported the generation of transgenic mice with a floxed β-geo/stop signal between a CMV promoter and the constitutively active intracellular domain of Notch1 (IC-Notch1) linked with a human placental alkaline phosphatase (hPLAP) reporter (ZAP-IC-Notch1). In this study, we examined the results of activating IC-Notch1 in endothelial cells. ZAP-IC‑Notch1 mice were crossed with Tie2-Cre mice to activate IC-Notch1 expression specifically in endothelial cells. The ZAP-IC-Notch1/Tie2-Cre double transgenic embryos died at E9.5-10.5 with disruption of vasculature and enlargement of myocardium. VE-cadherin expression was decreased and EphrinB2 expression was increased in the heart of these embryos. Mesenchymal cell marker α-smooth muscle actin (SMA) was expressed in IC-Notch1‑expressing endothelial cells. In addition, upregulation of Snail, the key effector in mediating EndoMT, was identified in the cardiac cushion of the double transgenic murine embryo heart. The results of the present study demonstrate that constitutively active Notch signaling promotes EndoMT and differentially regulates endothelial/mesenchymal cell markers during cardiac development.

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