EGFL7 Is Expressed in Bone Microenvironment and Promotes Angiogenesis via ERK, STAT3, and Integrin Signaling Cascades
EGFL7 Is Expressed in Bone Microenvironment and Promotes Angiogenesis via ERK, STAT3, and Integrin Signaling Cascades
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DOI：
10.1002/jcp.24684
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发表时间：
2015-01-01
影响因子：
5.6
通讯作者：
Xu, Jiake
中科院分区：
文献类型：
--
作者：
Chim, Shek Man;Kuek, Vincent;Xu, Jiake
血管生成在骨形成、重塑和骨折愈合中起着关键作用。骨微环境中血管生成的调节非常复杂，并由骨细胞和内皮细胞之间的细胞间通讯协调。在这里，我们报道了表皮生长因子（EGF）重复蛋白超家族的成员EGF样结构域7（EGFL7）在破骨细胞和成骨细胞谱系中表达，并促进内皮细胞活性。添加外源重组 EGFL7 可增强 SVEC（猿病毒 40 转化的小鼠微血管内皮细胞系）细胞迁移和体外管状结构形成。此外，重组 EGFL7 在离体胎儿小鼠跖骨血管生成测定中促进具有网状结构的血管生成。我们发现重组 EGFL7 诱导 SVEC 细胞中细胞外信号调节激酶 1/2 (ERK1/2)、信号转导子和转录激活子 3 (STAT3) 以及粘着斑激酶 (FAK) 的磷酸化。抑制 ERK1/2 和 STAT3 信号传导会损害 EGFL7 诱导的内皮细胞迁移和胎儿小鼠跖骨外植体中的血管生成。生物信息学分析表明，EGFL7 含有保守的 RGD/QGD 基序，并且在 RGD 肽存在的情况下，EGFL7 诱导的内皮细胞迁移显着减少。此外，EGFL7基因表达在生长板损伤修复过程中显着上调。总之，这些结果表明骨细胞表达的 EGFL7 通过整合素介导的信号传导调节内皮细胞活性。这项研究强调了EGFL7与EGFL6一样，在骨微环境中表达，在骨血管生成的调节中发挥着重要作用。 J.细胞。生理学。 229：82-94，2014 年。(c) 2014 年 Wiley 期刊公司。
Angiogenesis plays a pivotal role in bone formation, remodeling, and fracture healing. The regulation of angiogenesis in the bone microenvironment is highly complex and orchestrated by intercellular communication between bone cells and endothelial cells. Here, we report that EGF-like domain 7 (EGFL7), a member of the epidermal growth factor (EGF) repeat protein superfamily is expressed in both the osteoclast and osteoblast lineages, and promotes endothelial cell activities. Addition of exogenous recombinant EGFL7 potentiates SVEC (simian virus 40-transformed mouse microvascular endothelial cell line) cell migration and tube-like structure formation in vitro. Moreover, recombinant EGFL7 promotes angiogenesis featuring web-like structures in ex vivo fetal mouse metatarsal angiogenesis assay. We show that recombinant EGFL7 induces phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells. Inhibition of ERK1/2 and STAT3 signaling impairs EGFL7-induced endothelial cell migration, and angiogenesis in fetal mouse metatarsal explants. Bioinformatic analyses indicate that EGFL7 contains a conserved RGD/QGD motif and EGFL7-induced endothelial cell migration is significantly reduced in the presence of RGD peptides. Moreover, EGFL7 gene expression is significantly upregulated during growth plate injury repair. Together, these results demonstrate that EGFL7 expressed by bone cells regulates endothelial cell activities through integrin-mediated signaling. This study highlights the important role that EGFL7, like EGFL6, expressed in bone microenvironment plays in the regulation of angiogenesis in bone. J. Cell. Physiol. 229: 82-94, 2014. (c) 2014 Wiley Periodicals, Inc.