Impairment of endothelial‐mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos
Impairment of endothelial‐mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos
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DOI：
10.1002/dvdy.24216
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发表时间：
2015-01
影响因子：
2.5
通讯作者：
Ken Mizuta;Masahide Sakabe;Aya Hashimoto;Tomoko Ioka;C. Sakai;Kazuki Okumura;Miwa Hattammaru;Masahide Fujita;Mutsumi Araki;Satoshi Somekawa;Yoshihiko Saito;O. Nakagawa
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文献类型：
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作者：
Ken Mizuta;Masahide Sakabe;Aya Hashimoto;Tomoko Ioka;C. Sakai;Kazuki Okumura;Miwa Hattammaru;Masahide Fujita;Mutsumi Araki;Satoshi Somekawa;Yoshihiko Saito;O. Nakagawa
背景：内皮-间质转化（EndMT）是心脏形态发生过程中内皮细胞垫形成的关键。我们最近确定Tmem 100作为血管发育不可或缺的内皮基因。在这项研究中，我们进一步研究了EndMT在房室通道（AVC）垫形成过程中的作用。结果：Tmem 100在AVC内膜细胞中表达，Tmem 100缺失胚胎在AVC垫中出现严重的EndMT缺陷。虽然AVC心肌中血管内皮生长因子（VEGF）表达的钙调磷酸酶依赖性抑制对EndMT很重要，但在Tmem 100无效心脏中观察到Vegfa表达显著上调。在Tmem 100 null AVC外植体中受损的EndMT通过组成型活性钙调磷酸酶A的表达而部分但显著地恢复，这表明在Tmem 100 null心脏中心肌钙调磷酸酶-VEGF信号传导失调。此外，移植培养物中的Tmem 100无效内皮细胞对心肌源性生长因子、转化生长因子β2和骨形态发生蛋白2处理没有显示EndMT，表明EndMT缺陷机制中涉及额外的内皮细胞特异性异常。Tmem 100基因敲除胚胎的内皮细胞中NFATc 1核转位的缺乏表明内皮细胞钙信号传导受损。结论：Tmem 100缺陷可能通过干扰多种钙相关信号传导事件导致AVC垫形成期间的EndMT缺陷。发展动力学244：31-42，2015年。© 2014 Wiley Periodicals，Inc.
Background: Endothelial‐mesenchymal transformation (EndMT) is essential for endocardial cushion formation during cardiac morphogenesis. We recently identified Tmem100 as an endothelial gene indispensable for vascular development. In this study, we further investigated its roles for EndMT during atrioventricular canal (AVC) cushion formation. Results: Tmem100 was expressed in AVC endocardial cells, and Tmem100 null embryos showed severe EndMT defect in the AVC cushions. While calcineurin‐dependent suppression of vascular endothelial growth factor (VEGF) expression in the AVC myocardium is important for EndMT, significant up‐regulation of Vegfa expression was observed in Tmem100 null heart. EndMT impaired in Tmem100 null AVC explants was partially but significantly restored by the expression of constitutively‐active calcineurin A, suggesting dysregulation of myocardial calcineurin‐VEGF signaling in Tmem100 null heart. Moreover, Tmem100 null endocardial cells in explant culture did not show EndMT in response to the treatment with myocardium‐derived growth factors, transforming growth factor β2 and bone morphogenetic protein 2, indicating involvement of an additional endocardial‐specific abnormality in the mechanism of EndMT defect. The lack of NFATc1 nuclear translocation in endocardial cells of Tmem100 null embryos suggests impairment of endocardial calcium signaling. Conclusions: The Tmem100 deficiency causes EndMT defect during AVC cushion formation possibly via disturbance of multiple calcium‐related signaling events. Developmental Dynamics 244:31–42, 2015. © 2014 Wiley Periodicals, Inc.