Abstract
Chronic inflammation promotes endothelial plasticity, leading to the development of several diseases, including fibrosis and cancer in numerous organs. The basis of those processes is a phenomenon called the endothelial–mesenchymal transition (EndMT), which results in the delamination of tightly connected endothelial cells that acquire a mesenchymal phenotype. EndMT-derived cells, known as the myofibroblasts or cancer-associated fibroblasts (CAFs), are characterized by the loss of cell–cell junctions, loss of endothelial markers, and gain in mesenchymal ones. As a result, the endothelium ceases its primary ability to maintain patent and functional capillaries and induce new blood vessels. At the same time, it acquires the migration and invasion potential typical of mesenchymal cells. The observed modulation of cell shape, increasedcell movement, and invasion abilities are connected with cytoskeleton reorganization. This paper focuses on the review of current knowledge about the molecular pathways involved in the modulation of each cytoskeleton element (microfilaments, microtubule, and intermediate filaments) during EndMT and their role as the potential targets for cancer and fibrosis treatment.
Highlights
The vascular endothelium is composed of a monolayer of tightly connected endothelial cells that cover the interior surface of blood vessels
There is a growing amount of evidence that endothelial cells can serve as sources of myofibroblasts in fibrosis, such as cystic, kidney, heart, dermal, pulmonary, and intestinal fibrosis, as well as cancerassociated fibroblasts (CAFs) in neoplasia [5,6,7,8,9,10,11,12,13,14,15]
They are characterized as α-smooth muscle actin (α-SMA)-positive myofibroblasts, which are the principal source of the enormous extracellular matrix (ECM), including collagen type I, fibronectin, hyaluronan, and elastin [19,20,21]
Summary
The endothelial–mesenchymal transition (EndMT) was initially observed during heart development [23,24]. Reactive oxygen species (ROS) works by differential pathways They are able to induce TGF-β expression and, via a positive feedback loop, lead to ROS production. The in vivo and organ-in-chip experiments have shown that high shear stress appears to inhibit EndMT [41] via extracellularsignal-regulated kinase 5 (ERK5), whereas ERK5 overactivation prevents the EndMT in cells exposed to a disturbed flow or are stimulated by TGF-β under static conditions [45]. Different mechanical stresses, termed cyclic strain, and caused by a perpendicular stretching force on the vessel wall, have been shown to potentiate the EndMT by augmenting both TGF-β and Wnt signaling [42,43]. High glucose concentrations have been shown to cause EndMT, involving extracellular signal-regulated kinase (ERK) 1/2 phosphorylation.
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