ArticleMolecular biology of the cell2004
Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts.
Article in Molecular biology of the cell, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 138 papers, 1 of them a synthesis that pooled it.
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Who cites it
138 citing papers in PubMed, 1 synthesis or guideline pooled it, 348 citations in OpenAlex.
- Dissecting the Genetic Architecture of Intracranial Aneurysms.Circulation. Genomic and precision medicine · 2025Pooled it
- Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis.Annals of the rheumatic diseases · 2018Trial
- Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension.Respiratory research · 2009Trial
- Clazosentan Attenuates Endothelin-1-Induced ETA Protein Upregulation and Contractile Sensitization in Brain Pericytes.Pharmaceutics · 2026Article
- Targeting Cardiac Fibroblast Plasticity for Antifibrotic and Regenerative Therapy in Heart Failure.Cells · 2026Review
- Targeting IL6-Edn1-FoxO1 axis enables lung growth in mechanically ventilated newborn mice.The European respiratory journal · 2025Article
- Endothelin-1 as a Candidate Biomarker of Systemic Sclerosis: A GRADE-Assessed Systematic Review and Meta-Analysis With Meta-Regression.Biomarker insights · 2025Article
- Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition.Biomedicines · 2024Review
- Clinical, Histologic, and Transcriptomic Evaluation of Sequential Fat Grafting for Morphea: A Nonrandomized Controlled Trial.JAMA dermatology · 2024Article
- Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of ATInternational journal of molecular sciences · 2023Article
- Stretching Promotes Wound Contraction Through Enhanced Expression of Endothelin Receptor B and TRPC3 in Fibroblasts.Plastic and reconstructive surgery. Global open · 2023Article
- Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ETInternational journal of molecular sciences · 2023Article
- Pathogenic Mechanisms of Pulmonary Arterial Hypertension: Homeostasis Imbalance of Endothelium-Derived Relaxing and Contracting Factors.JACC. Asia · 2022Review
- Review
- The role of endothelin and RAS/ERK signaling in immunopathogenesis-related fibrosis in patients with systemic sclerosis: an updated review with therapeutic implications.Arthritis research & therapy · 2022Review
- PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis.Angiogenesis · 2022Article
- Review
- Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis.Frontiers in pharmacology · 2022Review
- Protective Effects of Endothelin-2 Expressed in Epithelial Cells on Bleomycin-Induced Pulmonary Fibrosis in Mice.The Kobe journal of medical sciences · 2021Article
- Tauroursodeoxycholic Acid Decreases Keloid Formation by Reducing Endoplasmic Reticulum Stress as Implicated in the Pathogenesis of Keloid.International journal of molecular sciences · 2021Article
78 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including alpha-smooth muscle actin (alpha-SMA), ezrin, moesin, and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA, ezrin, paxillin, and moesin and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of alpha-SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma) show enhanced ET-1 expression and binding. Systemic sclerosis lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins alpha-SMA, ezrin, paxillin, and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.