Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation

被引:270
作者
Noseda, M
McLean, G
Niessen, K
Chang, L
Pollet, I
Montpetit, R
Shahidi, R
Dorovini-Zis, K
Li, LH
Beckstead, B
Durand, RE
Hoodless, PA
Karsan, A [1 ]
机构
[1] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada
[2] Univ British Columbia, Expt Med Program, Vancouver, BC V6T 2B5, Canada
[3] British Columbia Canc Agcy, Dept Med Biophys, Terry Fox Res Labs, Vancouver, BC, Canada
[4] British Columbia Canc Agcy, Dept Pathol & Lab Med, Vancouver, BC, Canada
[5] Univ British Columbia, Dept Pathol, Div Neuropathol, Vancouver, BC, Canada
[6] Vancouver Hosp & Hlth Sci Ctr, Vancouver, BC, Canada
[7] Stowers Inst Med Res, Stem Cell Res Lab, Kansas City, MO USA
[8] Univ Washington, Dept Bioengn, Seattle, WA USA
关键词
endothelial-to-mesenchymal transformation; Notch; Jagged1; endocardial cushion;
D O I
10.1161/01.RES.0000124300.76171.C9
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Various studies have identified a critical role for Notch signaling in cardiovascular development. In this and other systems, Notch receptors and ligands are expressed in regions that undergo epithelial-to-mesenchymal transformation. However, there is no direct evidence that Notch activation can induce mesenchymal transdifferentiation. In this study we show that Notch activation in endothelial cells results in morphological, phenotypic, and functional changes consistent with mesenchymal transformation. These changes include downregulation of endothelial markers (vascular endothelial [VE]-cadherin, Tie1, Tie2, platelet-endothelial cell adhesion molecule-1, and endothelial NO synthase), upregulation of mesenchymal markers (alpha-smooth muscle actin, fibronectin, and platelet-derived growth factor receptors), and migration toward platelet-derived growth factor-BB. Notch-induced endothelial-to-mesenchymal transformation does not seem to require external regulation and is restricted to cells expressing activated Notch. Jagged1 stimulation of endothelial cells induces a similar mesenchymal transformation, and Jagged1, Notch1, and Notch4 are expressed in the ventricular outflow tract during stages of endocardial cushion formation. This is the first evidence that Jagged1-Notch interactions induce endothelial-to-mesenchymal transformation, and our findings suggest that Notch signaling may be required for proper endocardial cushion differentiation and/or vascular smooth muscle cell development.
引用
收藏
页码:910 / 917
页数:8
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