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Cited by 243Systemic Sclerosis and Related DiseasesNitric Oxide and Endothelin EffectsTGF-β signaling in diseases

Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1

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Shi-wen, Xu, Denton, Christopher P., Holmes, Alan M., Black, Carol M., Abraham, David J., Dashwood, Michael R., Bou-Gharios, George, Pearson, Jeremy D.·2001·Journal of Investigative Dermatology
DOI 10.1046/j.1523-1747.2001.01256.x
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Abstract

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosis fibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.

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  • Differentially regulated genes included vascular wall mediators such as COL4A1, COL3A1, and FN1.

    “The differentially regulated genes included several mediators of vascular wall integrity and structure, such as COL4A1, COL3A1, and FN1 (Figure S4E), which may be downstream effects of increased EDN1 expression in the G/G ESC-ECs (Amiri et al., 2004; Shi-Wen et al., 2001).”

    From A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression (2017) · cites this paper as Shi-Wen et al., 2001

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Authors
Shi-wen, X., Denton, C. P., Holmes, A. M., Black, C. M., Abraham, D. J., Dashwood, M. R., Bou-Gharios, G., & Pearson, J. D.
Affiliations
  • The Royal Free Hospital (GB)
  • King's College London (GB)
Corresponding author
Abraham, David J.
ORCID
Venue
Journal of Investigative Dermatology
Publisher
Elsevier BV
Published
2001-03
Volume
116
Issue
3
Pages
417-425
ISSN
0022-202X (ISSN-L)
DOI
10.1046/j.1523-1747.2001.01256.x
OpenAlex
W2064485592
Cited by
243
References
35
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 10 · 2015: 13 · 2014: 11 · 2013: 12 · 2012: 6
FWCI
5.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Investigative Dermatology (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
endothelin-1, systemic sclerosis, fibroblasts, extracellular matrix remodeling, collagen synthesis, type I collagen, type III collagen, fibronectin, MMP-1, ETA receptor, endothelin B receptor, connective tissue fibrosis, tyrosine kinase inhibitors, protein kinase C
MeSH terms
Cells, Cultured, Collagen, Connective Tissue, Extracellular Matrix, Fibroblasts, Humans, Reference Values, RNA, Messenger, Scleroderma, Systemic, Transcription, Genetic, Gene Expression, Receptors, Endothelin, Endothelin-1, Matrix Metalloproteinase 1, Receptor, Endothelin A, Receptor, Endothelin B

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