Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany.
Institute for Physiological Chemistry and Pathobiochemistry, Excellence Cluster Cell-in-Motion, 48149 Münster, Germany.
Cardiovasc Res. 2015 May 1;106(2):284-94. doi: 10.1093/cvr/cvv098. Epub 2015 Mar 5.
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.
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.
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.
分泌型模块钙结合蛋白 1（SMOC1）是一种细胞外基质蛋白，可能干扰生长因子受体信号转导。本研究旨在确定其在血管内皮细胞中的表达如何受到调节及其在调节内皮细胞功能中的作用。
天然小鼠内皮细胞以及培养的人、猪和鼠内皮细胞均表达 SMOC1。缺氧通过下调 miR-223 增加培养细胞中的 SMOC1 表达，miR-223 缺失小鼠的肺部 SMOC1 表达增加。沉默 SMOC1（小干扰 RNA）可减弱体外血管生成试验中内皮细胞的增殖、迁移和发芽。同样，SMOC1(+/-) 小鼠的主动脉环体外发芽以及体内出生后视网膜血管生成也受到抑制。在血管内皮细胞中，转化生长因子 (TGF)-β 通过激活素样激酶 (ALK)5 信号转导导致静止，而 TGF-β 通过 ALK1 信号转导导致内皮细胞激活。SMOC1 作为 ALK5/SMAD2 信号的负调节剂，导致 α2 整合素水平改变。在机制上，SMOC1 与内胚层蛋白（endoglin）相关（免疫组织化学、邻近连接分析和共免疫沉淀）；内胚层蛋白是 TGF-β 超家族的一种内皮特异性 III 型辅助受体，SMOC1 下调对 SMAD2 磷酸化的影响被内胚层蛋白下调所消除。
这些结果表明，SMOC1 是内皮细胞产生的 ALK5 拮抗剂，可将 TGF-β 信号转导转向 ALK1 激活，从而促进内皮细胞增殖和血管生成。
