Role of secreted modular calcium-binding protein 1 (SMOC1) in transforming growth factor β signalling and angiogenesis
Abstract
AIMS: Secreted modular calcium-binding protein 1 (SMOC1) is a matricellular protein that potentially interferes with growth factor receptor signalling. The aim of this study was to determine how its expression is regulated in endothelial cells and its role in the regulation of endothelial cell function. METHODS AND RESULTS: SMOC1 was expressed by native murine endothelial cells as well as by cultured human, porcine, and murine endothelial cells. SMOC1 expression in cultured cells was increased by hypoxia via the down-regulation of miR-223, and SMOC1 expression was increased in lungs from miR-223-deficient mice. Silencing SMOC1 (small interfering RNA) attenuated endothelial cell proliferation, migration, and sprouting in in vitro angiogenesis assays. Similarly endothelial cell sprouting from aortic rings ex vivo as well as postnatal retinal angiogenesis in vivo was attenuated in SMOC1(+/-) mice. In endothelial cells, transforming growth factor (TGF)-β signalling via activin-like kinase (ALK) 5 leads to quiescence, whereas TGF-β signalling via ALK1 results in endothelial cell activation. SMOC1 acted as a negative regulator of ALK5/SMAD2 signalling, resulting in altered α2 integrin levels. Mechanistically, SMOC1 associated (immunohistochemistry, proximity ligation assay, and co-immunoprecipitation) with endoglin; an endothelium-specific type III auxiliary receptor for the TGF-β super family and the effects of SMOC1 down-regulation on SMAD2 phosphorylation were abolished by the down-regulation of endoglin. CONCLUSION: These results indicate that SMOC1 is an ALK5 antagonist produced by endothelial cells that tips TGF-β signalling towards ALK1 activation, thus promoting endothelial cell proliferation and angiogenesis.
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SMOC1 belongs to a family of matricellular proteins including SPARC, SMOC2, and testican-1.
“SMOC1 belongs to a family of matricellular proteins including secreted protein acidic and rich in cysteine (SPARC), SMOC2, and testican-1 [267].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [267]
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- Authors
- Awwad, K., Hu, J., Shi, L., Mangels, N., Abdel Malik, R., Zippel, N., Fisslthaler, B., Eble, J. A., Pfeilschifter, J., Popp, R., & Fleming, I.
- Affiliations
- Goethe University Frankfurt (DE)
- University of Münster (DE)
- University Hospital Frankfurt (DE)
- Corresponding author
- Fleming, Ingrid
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-03-06
- Volume
- 106
- Issue
- 2
- Pages
- 284-294
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- OpenAlex
- W1982494697
- Cited by
- 77
- References
- 56
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 13 · 2020: 10 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 2 · 2015: 1
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 1039/A6, SFB-1039, Exzellenzcluster 147, 834/A9, SFB,834)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- SMOC1, matricellular proteins, TGF-beta signaling, angiogenesis, endothelial cells, ALK5, ALK1, CD105, Smad2 phosphorylation, miR-223, hypoxia, endothelial cell proliferation, endothelial cell migration, retinal angiogenesis, integrin alpha2
- MeSH terms
- Animals, Endothelium, Vascular, Mice, Inbred C57BL, Mice, Transgenic, Swine, Signal Transduction, Osteonectin, Transforming Growth Factor beta, Receptors, Transforming Growth Factor beta, Neovascularization, Physiologic, Activin Receptors, Type I, Activin Receptors, Type II, Endothelial Cells, Cell Proliferation
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