The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?

Manetti, Mirko; Guiducci, Serena; Matucci‐Cerinic, Marco

doi:10.1002/art.30316

Cited by 26 publications

(27 citation statements)

References 30 publications

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“…Indeed, endothelial dysfunction is considered a pivotal factor contributing to peripheral vessel remodelling in SSc 3 15 41. A defective response to proangiogenic stimuli and several functional defects, such as an impaired ability to organise into capillary-like tubes in vitro, have been extensively reported in SSc-dMVECs 28 29 35 41 46.…”

Section: Discussionmentioning

confidence: 99%

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

et al. 2017

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“…These observations suggest that targeting components of these pathways may be a feasible therapeutic goal to modify crucial steps in the development of SSc fibroproliferative vasculopathy [208]. Furthermore, the important role that miRNAs have been shown to play in the regulation of gene expression has clearly opened the possibility of developing a novel therapeutic approach for SSc by targeting these extremely versatile noncoding RNA species.…”

Section: Discussionmentioning

confidence: 99%

Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis

2013

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The pathogenesis of Systemic Sclerosis (SSc) is extremely complex, and despite extensive studies, the exact mechanisms involved are not well understood. Numerous recent studies of early events in SSc pathogenesis have suggested that unknown etiologic factors in a genetically receptive host trigger structural and functional microvascular endothelial cell abnormalities. These alterations result in the attraction, transmigration, and accumulation of immune and inflammatory cells in the perivascular tissues, which in turn induce the phenotypic conversion of endothelial cells and quiescent fibroblasts into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndoMT. The activated myofibroblasts are the effector cells responsible for the severe and frequently progressive fibrotic process and the fibroproliferative vasculopathy that are the hallmarks of SSc. Thus, according to this hypothesis the endothelial and vascular alterations, which include the phenotypic conversion of endothelial cells into activated myofibroblasts, play a crucial role in the development of the progressive fibrotic process affecting skin and multiple internal organs. The role of endothelial cell and vascular alterations, the potential contribution of endothelial to mesenchymal cell transition in the pathogenesis of the tissue fibrosis, and fibroproliferative vasculopathy in SSc will be reviewed here.

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“…Human skin fibroblasts were serum-starved overnight using DMEM 0.1% BSA, plated at 5 3 10 3 cells/well in 96-well plates, and incubated with cell culture medium alone or with specific agonists (ATF-uPA [ 2 . At the end of the incubation, 20 ml/well CellTiter-96 was added.…”

Section: Proliferation Assaymentioning

confidence: 99%

“…and despite a number of studies that examined several aspects of its intricate picture, the mechanisms involved are still largely unknown. During the past decade, considerable attention has been paid to the origin of myofibroblast, the mesenchymal cell type most responsible for the excessive matrix production and deposition in tissue and vessel wall, found in fibrotic disorders and fibroproliferative vasculopathies (2). However, in SSc, the origin of myofibroblasts has not been completely elucidated (3).…”

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Upregulation of the N-Formyl Peptide Receptors in Scleroderma Fibroblasts Fosters the Switch to Myofibroblasts

Rossi

Napolitano

Pesapane

et al. 2015

The Journal of Immunology

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Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis. N-Formyl peptide (fMLF) receptors (FPRs) are chemotactic receptors involved in inflammation. Three FPRs have been identified: FPR1, FPR2, and FPR3. We have examined, by RT-PCR, Western blot and immunohistochemistry, FPRs expression in skin fibroblasts from 10 normal subjects and 10 SSc patients, showing increased expression in SSc fibroblasts. Several functions of FPRs occur through the interaction with a region of the urokinase-type plasminogen activator receptor (uPAR88–92), able to interact with FPRs and to mediate urokinase (uPA) or fMLF-dependent cell migration. Soluble uPAR84–95 peptide can act as a direct ligand of FPRs. Furthermore, uPA or its aminoterminal fragment (ATF) can promote the exposure of the uPAR88–92 region. The WKYMVm peptide is a FPRs pan-agonist. We investigated the functional effects of these agonists on normal and SSc fibroblasts. ATF, uPAR84–95, and WKYMVm regulated adhesion, migration, and proliferation of normal fibroblasts. Despite FPR overexpression, the response of SSc fibroblasts to the same agonists was greatly reduced, except for the proliferative response to ATF. SSc fibroblasts showed increased α-smooth muscle actin expression and improved capability to induce wound closure. Indeed, they overexpressed a cleaved uPAR form, exposing the uPAR88–92 region, and vitronectin, both involved in fibrosis and in the fibroblast-to-myofibroblast transition. FPR stimulation promoted α-smooth muscle actin expression in normal fibroblasts as well as motility, matrix deposition, αvβ5 integrin expression, and radical oxygen species generation in normal and SSc fibroblasts. This study provides evidence that FPRs may play a role in fibrosis and in the fibroblast-to-myofibroblast transition.

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The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?

Cited by 26 publications

References 30 publications

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis

Upregulation of the N-Formyl Peptide Receptors in Scleroderma Fibroblasts Fosters the Switch to Myofibroblasts

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