The contribution of endothelial cells to tissue fibrosis

Abstract

Purpose of review Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity and mortality rates. Growing evidence indicates that common cellular and molecular mechanisms may drive fibrosis of diverse cause and affecting different organs. The scope of this review is to highlight recent findings in support for an important role of vascular endothelial cells in the pathogenesis of fibrosis, with a special focus on systemic sclerosis as a prototypic multisystem fibrotic disorder. Recent findings Although transition of fibroblasts to chronically activated myofibroblasts is widely considered the central profibrotic switch, the endothelial cell involvement in development and progression of fibrosis has been increasingly recognized over the last few years. Endothelial cells can contribute to the fibrotic process either directly by acting as source of myofibroblasts through endothelial-to-myofibroblast transition (EndMT) and concomitant microvascular rarefaction, or indirectly by becoming senescent and/or secreting a variety of profibrotic and proinflammatory mediators with consequent fibroblast activation and recruitment of inflammatory/immune cells that further promote fibrosis. Summary An in-depth understanding of the mechanisms underlying EndMT or the acquisition of a profibrotic secretory phenotype by endothelial cells will provide the rationale for novel endothelial cell reprogramming-based therapeutic approaches to prevent and/or treat fibrosis.

Melatonin alleviates myocardial dysfunction through inhibition of endothelial‐to‐mesenchymal transition via the NF‐κB pathway

“…EndMT is a biological process in which the cell transitions from an endothelial phenotype to a mesenchymal‐like phenotype 4 . In fact, a significant proportion of fibroblasts originates from ECs, indicating that EndMT plays a crucial role in differentiating pro‐fibrotic myofibroblasts in the pathogenesis of cardiac fibrotic diseases 29 . However, uncontrolled EndMT process can be triggered in pathological conditions, such as inflammation and oxidative stress, particularly in infarcted areas 11 …”

Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis

“…EC dysfunction plays a pivotal role in the development of SSc vasculopathy, and the initial damage affecting these cells can be induced by various factors including environmental factors, viral infections, anti-endothelial autoantibodies, ischemia-reperfusion events, and reactive oxygen species [ 2 , 6 , 12 , 13 ]. Once injured, ECs can undergo different outcomes such as dysfunctional activation or apoptosis.…”

“…When dysfunctionally activated, ECs are incapable of performing angiogenesis, and, releasing higher levels of endothelin-1 (ET-1) and lower levels of nitric oxide and prostacyclin, leads to an imbalance that finally results in vasospasm, intimal proliferation, and vascular wall fibrosis [ 2 , 6 , 12 ]. Furthermore, activated ECs also exhibit changes in their cytoskeleton, loss of tight junctions, and the increased expression of adhesion molecules and cytokines, all of which promote interactions with circulating inflammatory/immune cells and contribute to perivascular inflammation [ 2 , 6 , 12 ]. Additionally, these cells can cause platelet activation and intravascular fibrin deposition, ultimately leading to luminal narrowing, vessel occlusion, and tissue hypoxia [ 2 , 6 , 12 ].…”

“…Furthermore, activated ECs also exhibit changes in their cytoskeleton, loss of tight junctions, and the increased expression of adhesion molecules and cytokines, all of which promote interactions with circulating inflammatory/immune cells and contribute to perivascular inflammation [ 2 , 6 , 12 ]. Additionally, these cells can cause platelet activation and intravascular fibrin deposition, ultimately leading to luminal narrowing, vessel occlusion, and tissue hypoxia [ 2 , 6 , 12 ]. Conversely, EC apoptosis results in the loss of peripheral microcirculation, leading to a chronic state of tissue ischemia that cannot be compensated by sufficient angiogenesis [ 2 , 6 , 12 ].…”

“…Additionally, these cells can cause platelet activation and intravascular fibrin deposition, ultimately leading to luminal narrowing, vessel occlusion, and tissue hypoxia [ 2 , 6 , 12 ]. Conversely, EC apoptosis results in the loss of peripheral microcirculation, leading to a chronic state of tissue ischemia that cannot be compensated by sufficient angiogenesis [ 2 , 6 , 12 ]. Besides EC activation and apoptosis, SSc defective angiogenesis and capillary loss can further result from EndoMT, a process during which ECs undergo a phenotypic change toward profibrotic myofibroblasts contributing to tissue fibrosis [ 12 , 14 ].…”