Abstract:
BACKGROUND:Systemic sclerosis (SSc) is characterized by early vascular abnormalities and subsequent fibroblast activation to myofibroblasts, leading to fibrosis. Recently, endothelial-to-mesenchymal transition (EndoMT), a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype, has been reported in SSc. In the present study, we evaluated the ability of endothelin-1 (ET-1) dual receptor antagonists bosentan (BOS) and macitentan (MAC) to antagonize EndoMT in vitro. METHODS:Ten women with limited SSc were enrolled. They underwent double skin biopsy (affected and nonaffected skin). Fibroblasts and microvascular endothelial cells (MVECs) were isolated from biopsies. We performed mono- or coculture of MVECs (isolated from nonaffected skin) with fibroblasts (isolated from affected skin and stimulated with ET-1 and transforming growth factor beta [TGF-β]). In cocultures, the MVEC layer was left undisturbed or was preincubated with BOS or MAC. After 48 h of coculture, MVECs were analyzed for their tube formation ability and for messenger RNA and protein expression of different vascular (CD31, vascular endothelial growth factor-A [VEGF-A], VEGF-A165b) and profibrotic (alpha-smooth muscle actin [α-SMA], collagen type I [Col I], TGF-β) molecules. RESULTS:After 48 h, MVECs showed a reduced tube formation ability when cocultured with SSc fibroblasts. CD31 and VEGF-A resulted in downregulation, while VEGF-A165b, the antiangiogenic isoform, resulted in upregulation. At the same time, mesenchymal markers α-SMA, Col I, and TGF-β resulted in overexpression in MVECs. Tube formation ability was restored when MVECs were preincubated with BOS or MAC, also reducing the expression of mesenchymal markers and restoring CD31 expression and the imbalance between VEGF-A and VEGF-A165b. CONCLUSIONS:With this innovative EndoMT in vitro model realized by coculturing nonaffected MVECs with affected SSc fibroblasts, we show that the presence of a myofibroblast phenotype in the fibroblast layer, coupled with an ET-1-TGF-β synergic effect, is responsible for EndoMT. BOS and MAC seem able to antagonize this phenomenon in vitro, confirming previous evidence of endothelium-derived fibrosis in SSc and possible pharmacological interference.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Corallo C,Cutolo M,Kahaleh B,Pecetti G,Montella A,Chirico C,Soldano S,Nuti R,Giordano Ndoi
10.1186/s13075-016-1122-ysubject
Has Abstractpub_date
2016-10-06 00:00:00pages
228issue
1eissn
1478-6354issn
1478-6362pii
10.1186/s13075-016-1122-yjournal_volume
18pub_type
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02324-7
更新日期:2020-10-15 00:00:00
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doi:10.1186/s13075-020-02386-7
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02218-8
更新日期:2020-06-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 社论
doi:10.1186/ar1450
更新日期:2004-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar1185
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02412-8
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4224
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3208
更新日期:2010-01-01 00:00:00
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更新日期:2010-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,meta分析
doi:10.1186/s13075-019-1847-5
更新日期:2019-02-22 00:00:00
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doi:10.1186/s13075-020-02354-1
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pub_type: 杂志文章,评审
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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更新日期:2011-01-05 00:00:00
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更新日期:2013-08-14 00:00:00
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