Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells.
Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells.
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DOI：
10.1161/atvbaha.113.300647
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Towler DA
中科院分区：
文献类型：
--
作者：
Cheng SL;Shao JS;Behrmann A;Krchma K;Towler DA
内皮细胞（EC）可经历内皮-间充质转化（EndMT）并伴有组织纤维化。Wnt和Msx 2调节信号参与动脉纤维化和钙化。我们研究了Wnt 7、Msx 2和Dkk 1-一种Wnt 7拮抗剂--对原代主动脉内皮细胞（AoEC）中EndMT的影响。用表达Dkk 1的载体转导AoEC抑制EC分化并诱导矿化肌成纤维细胞表型。Dkk 1抑制claudin 5、PECAM、钙粘蛋白5（Cdh 5）、Tie 1和Tie 2。Dkk 1将立方细胞单层转化为梭形多层，并抑制EC索形成。肌成纤维细胞和成骨标志物-SM 22，I型胶原，Osx，Runx 2，碱性磷酸酶-通过激活素样激酶/ Smad途径被Dkk 1上调。Dkk 1增加成骨条件下培养的AoEC的纤维化矿化-与间充质细胞反应相反。Msx 2和Wnt 7 b维持分化的EC的形态学和上调标记物。在Wnt 7 b（fl/fl）中用Cdh 5-Cre转基因删除EC Wnt 7 b;LDLR−/−小鼠上调主动脉成骨基因（Osx，Sox 9，Runx 2，Msx 2）和核pSmad 1/5，并增加胶原和钙积累。Dkk 1增强AoEC中的EndMT，而Wnt 7 b和Msx 2信号保持EC表型。EC对Dkk 1、Wnt 7 b和Msx 2的反应与间充质反应相反，在动脉硬化过程中，EC表型稳定性与骨纤维化倾向相结合。
Endothelial cells (ECs) can undergo an endothelial-mesenchymal transition (EndMT) with tissue fibrosis. Wnt- and Msx2-regulated signals participate in arteriosclerotic fibrosis and calcification. We studied the impact of Wnt7, Msx2, and Dkk1 – a Wnt7 antagonist -- on EndMT in primary aortic endothelial cells (AoECs). Transduction of AoECs with vectors expressing Dkk1 suppressed EC differentiation and induced a mineralizing myofibroblast phenotype. Dkk1 suppressed claudin 5, PECAM, cadherin 5 (Cdh5), Tie1 and Tie2. Dkk1 converted the cuboidal cell monolayer into a spindle-shaped multilayer and inhibited EC cord formation. Myofibroblast and osteogenic markers –SM22, type I collagen, Osx, Runx2, alkaline phosphatase -- were upregulated by Dkk1 via activin-like kinase / Smad pathways. Dkk1 increased fibrotic mineralization of AoECs cultured under osteogenic conditions – the opposite of mesenchymal cell responses. Msx2 and Wnt7b maintained morphology and upregulated markers of differentiated ECs. Deleting EC Wnt7b with the Cdh5-Cre transgene in Wnt7b(fl/fl);LDLR−/− mice upregulated aortic osteogenic genes (Osx, Sox9, Runx2, Msx2) and nuclear pSmad1/5, and increased collagen and calcium accumulation. Dkk1 enhances EndMT in AoECs, while Wnt7b and Msx2 signals preserve EC phenotype. EC responses to Dkk1, Wnt7b, and Msx2 are the opposite of mesenchymal responses, coupling EC phenotypic stability with osteofibrogenic predilection during arteriosclerosis.