Abstract
Around 45% of deaths in the EU and the US are due to fibrotic diseases. Although myofibroblasts are detected in various fibrotic tissues, they are mostly transdifferentiated from endothelial cells during the endothelial-mesenchymal transition (EndMT) induced by tumor growth factor-beta (TGF-β) family members. Growing evidence indicates that oxidative stress might enhance the sensitivity and the effects of TGF-β stimulation; however, the molecular mechanisms involved in the coordination of oxidative stress and TGF-β inductions remain poorly understood. Our findings indicate for the first time that oxidative stress enhances mesenchymal trans-differentiation of human microvascular endothelial cells (HMEC-1 cells) and that the oxidative stress-dependent TGF-β2-RhoA/Rac1-MRTF-A axis is critical for the induction of later stages of EndMT. This additive effect was manifested in TGF-β1-stimulated and Snail-overexpressed cells, where it caused higher cell elongation and faster migration on collagen I layers. Additionally, Western blot assay indicated the presence of alterations in cell contraction and EndMT markers. We conclude that complex anti-fibrotic therapies based on the inhibition of MRTF activities and oxidative stress might be an attractive target for fibrosis treatment.
Highlights
Fibrosis is characterized by the excessive accumulation of extracellular matrix proteins secreted by myofibroblasts in response to cellular damage
To examine the role of oxidative stress with endothelial-mesenchymal transition (EndMT) stimulation, HMEC-1 cells were incubated with 10 ng/mL TGF-β1 or TGF-β2 under 0.1, 1.0, or 5.0 μM H2O2 pressure
It has been found that TGF-β2 induces EndMT more strongly than TGF-β1, with their resulting respective elongation ratios being approximately 50% and 15% higher [15]
Summary
Fibrosis is characterized by the excessive accumulation of extracellular matrix proteins secreted by myofibroblasts in response to cellular damage. One of the crucial precursors of myofibroblast is endothelial cells (ECs), which undergo an endothelial-mesenchymal transition (EndMT) under the influence of cytokines and growth factors [3], mainly tumor growth factor-beta (TGF-β) family members [4,5]. EndMT-induced ECs demonstrate downregulation of endothelial markers like VE-cadherin, claudin, and zona-occludens 1 (ZO-1) and increased expression of typical mesenchymal markers, such as Fibroblast-specific protein 1 (FSP-1), alpha-smooth muscle actin (α-SMA), and N-cadherin. This process is regulated by transcription factors such as Snail, Slug, and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), whose levels are elevated during cellular transdifferentiation [6]. The mechanism of action of particular TGF-β forms remains unclear and seems to be dependent on cell origin [4,5]. It has been demonstrated that, in contrast to TGF-β1, with affected only the early stages of EndMT, TGF-β2 stimulates HMEC-1 cells to take a more elongated shape and significantly increase their modulation of endothelial and mesenchymal marker levels [5]
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