Khader Awwad1, Jiong Hu1, Lei Shi1, Nicole Mangels1, Randa Abdel Malik1, Nina Zippel1, Beate Fisslthaler1, Johannes A Eble2, Josef Pfeilschifter3, Rüdiger Popp1, Ingrid Fleming4. 1. Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany. 2. Institute for Physiological Chemistry and Pathobiochemistry, Excellence Cluster Cell-in-Motion, 48149 Münster, Germany. 3. Pharmacenter Frankfurt/ZAFES, Goethe-University Hospital, 60590 Frankfurt am Main, Germany. 4. Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany fleming@em.uni-frankfurt.de.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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