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Introduction
Endothelial-mesenchymal cell transdifferentiation (EndoMT) is the process in which endothelial cells lose their cell- type-specific characteristics and gain a mesenchymal or myofibroblastic phenotype (1). EndoMT may be initiated by cytokines or growth factors secreted by peri-vascular cells (2). The basement membrane under the endothelial cells is likely to be degraded by matrix metalloproteinases (MMPs), then the transitioning endothelial cells become motile and invade the surrounding tissues (3). During EndoMT, endothelial cells lose the expression of their markers, such as vascular endothelial (VE)-cadherin and von Willebrand factor (vWF), and gain the expression of mesenchymal cell markers including vimentin, α-smooth muscle actin (SMA) and type I collagen (1,2,4). EndoMT was first observed in studies on cardiac development (5,6). EndoMT has emerged as a possible mechanism in the pathogenesis of various diseases, including diabetic nephropathy, cardiac fibrosis, intestinal fibrosis, pulmonary hypertension and systemic sclerosis (7–10).
Despite the notable importance of EndoMT for embryonic development and pathologic conditions, the underlying molecular mechanisms involved in EndoMT have yet to be fully elucidated. Substantial evidence has indicated the crucial role of TGF-β signaling in the initiation of EndoMT (11). A number of signaling transduction pathways, including VEGF, NFAT, BMP, Wnt/β-catenin, ErbB, and NF1/Ras, play a role in EndoMT during cardiac development (12). In addition, EndoMT can be modulated in response to manipulations of the Notch pathways in many different endothelial cell types (13). It is also suggested that a number of signaling pathways interact with TGF-β and Notch to mediate EndoMT during heart valve development (14,15).
The Notch signaling pathway is evolutionarily conserved and plays a fundamental role in a number of mechanisms (16,17). Activation of Notch signaling is initiated through ligand-receptor interactions which lead to proteolytic cleavage of the receptor (18). Mammals have four receptors (Notch1, 2, 3, 4) and five ligands (Jagged 1 and 2, and δ-like 1, 3 and 4). Following activation, the intracellular domain of Notch (IC-Notch) translocates into the nucleus and binds the DNA-binding protein CSL (CBF1/suppressor of hairless/Lag-1) through its RAM23 domain (19). The CSL protein (also known as CBF-1/RBP-Jκ) binds to the DNA sequence GTGGGAA in the promoter region of Notch-regulated genes (20). The components of the Notch signaling pathway are crucial for cell fate decisions during morphogenesis and embryonic development (17,21). Notch...