Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases

Abstract

Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy have been mainly used as therapy owing to these characteristics, their effectiveness does not meet expectations. Therefore, a better understanding of the etiology and new therapeutic approaches are needed. Endothelial cells (ECs) line the inner walls of blood vessels and maintain vascular homeostasis by protecting vascular cells from pathological stimuli. Chronic stimulation of ECs by various factors, including pro-inflammatory cytokines and hypoxia, leads to ECs undergoing an imbalance of endothelial homeostasis, which results in endothelial dysfunction and is closely associated with vascular diseases. Emerging studies suggest that endothelial to mesenchymal transition (EndMT) contributes to endothelial dysfunction and plays a key role in the pathogenesis of vascular diseases. EndMT is a process by which ECs lose their markers and show mesenchymal-like morphological changes, and gain mesenchymal cell markers. Despite the efforts to elucidate these molecular mechanisms, the role of EndMT in the pathogenesis of lung disease still requires further investigation. Here, we review the importance of EndMT in the pathogenesis of pulmonary vascular diseases and discuss various signaling pathways and mediators involved in the EndMT process. Furthermore, we will provide insight into the therapeutic potential of targeting EndMT.

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

“…The increase in calpain-1/2 associated with Piezo1-driven Ca 2 þ influx may also contribute to the development of pulmonary vascular remodeling by inducing extracellular matrix remodeling, vascular fibrosis, and arterial calcification (47,49,50,88). Calpain may also activate TGF-b1 and AKT/mTORC2 signaling (50) and induce EndMT in PAECs (89)(90)(91).…”

Endothelial-to-mesenchymal transition in systemic sclerosis

“…The EndMT process was observed not only during physiological development [24,46] and wound healing [47], but also during pathological processes, characterized by fibrosis, vascular injury and inflammation [24–28]. The use of lineage tracing models, assessing the EndMT in vivo , confirmed the EC lineage conversion [48].…”

“…With regard to ECs, several reports [4,16,17] have confirmed the ability of these cells to transdifferentiate towards myofibroblasts through the endothelial‐to‐mesenchymal transition (EndMT), which is a non‐malignant phenomenon of cellular transdifferentiation by which ECs undergo a phonotypical differentiation, losing vascular ECs markers and gaining mesenchymal cell markers [2,18–22]. EndMT was first reported in studies on the physiological development of the heart [18,23] but, to date, this process is considered as a possible pathogenetic mechanism for different conditions, including cardiac fibrosis, kidney fibrosis, diabetic nephropathy, pulmonary hypertension and SSc [24–29]. Understanding the mechanism and functions of the EndMT process is pivotal to individuate early pathogenetic events and possibly new therapeutic targets for SSc in a very early phase, before the fibrotic process, which may be considered an end‐stage condition [10,30,31].…”

The Contribution of Endothelial-Mesenchymal Transition to Atherosclerosis

“…Therefore, ECs play an important role in maintaining vascular homeostasis and blood fluidity under various physiological processes. These cells can regulate vascular tone, permeability, homeostasis, coagulation, angiogenesis, and inflammatory responses via their cell adhesion molecules, cytokines, and chemokines [78][79][80]. The multiple functions of vascular endothelial cells are illustrated in Figure 3.…”