Endothelin-1, via ET A Receptor and Independently of Transforming Growth Factor-β, Increases the Connective Tissue Growth Factor in Vascular Smooth Muscle Cells
Abstract
Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardiovascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in vascular fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1–treated cells, showing that CTGF participates in ET-1–induced ECM accumulation. The ET A , but not ET B , antagonist diminished ET-1–induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ET A receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-β– and angiotensin (Ang) II–induced fibrosis. In VSMCs, ET-1 did not upregulate TGF-β gene or protein. The presence of neutralizing transforming growth factor (TGF)-β antibody did not modify ET-1–induced CTGF production, showing a TGF-β–independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ET A antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-β and through the activation of several intracellular signals via ET A receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in vascular diseases.
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EDNRA encodes the endothelin receptor type A (ET-A) that interacts with receptor type B to mediate endothelin-1 signaling.
“EDNRA encodes the endothelin receptor type A (ET-A) that interacts with receptor type B to mediate endothelin-1 (ET-1) signaling, a potent endothelium-derived vasoconstrictor peptide that can activate vascular smooth muscle cells, inducing proliferation, and synthesis of ECM proteins [35].”
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References 49 · Cited by 119
Research works printed but not linked: 3
- Mori T, Kawara S, Shinozakai M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K. Role and interaction of connective tissue growth factor with transforming growth factor beta in persistent fibrosis: a mouse model of fibrosis. J Cell Physiol. 1999;181:153-159.
- Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J. Angiotensin II activates nuclear transcription factor B through AT1 and AT2 receptors in cultured vascular smooth muscle cells. Molecular mechanisms. Circ Res. 2000;23:1266 -1272.
- Fraccarollo D, Galuppo P, Bauersachs J, Ertl G. Collagen accumu- lation after myocardial infarction: effects of ETA receptor blockade and implications for early remodeling. Cardiovasc Res. 2002;54: 559 -567.
- Authors
- Rodriguez-Vita, J., Ruiz-Ortega, M., Rupérez, M., Esteban, V., Sanchez-López, E., Plaza, J. J., & Egido, J.
- Affiliations
- From the Vascular and Renal Research Laboratory, Fundación Jiménez Diaz, Universidad Autónoma Madrid, Spain
- Venue
- Circulation Research
- Published
- 2005-07-22
- Volume
- 97
- Issue
- 2
- Pages
- 125-134
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2134734822
- Cited by
- 119
- References
- 49
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 7 · 2014: 6 · 2013: 10 · 2012: 6
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Keywords
- endothelin-1, connective tissue growth factor, vascular smooth muscle cells, ETA receptor, vascular fibrosis, extracellular matrix accumulation, angiotensin II, RhoA/ROCK signaling, mitogen-activated protein kinase, reactive oxygen species, fibrosis
- MeSH terms
- Angiotensin I, Animals, Cells, Cultured, Gene Expression Regulation, Muscle, Smooth, Vascular, Promoter Regions, Genetic, Rats, Inbred WKY, RNA, Messenger, 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt, Transforming Growth Factor beta, Extracellular Matrix Proteins, Immediate-Early Proteins, Endothelin-1, rhoA GTP-Binding Protein, Intercellular Signaling Peptides and Proteins, Receptor, Endothelin A, Extracellular Signal-Regulated MAP Kinases, Rats, Connective Tissue Growth Factor
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