Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis.
Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis.
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DOI：
10.1161/circresaha.115.304379
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发表时间：
2014-10-24
影响因子：
20.1
通讯作者：
Hatcher CJ
中科院分区：
文献类型：
--
作者：
Diman NY;Brooks G;Kruithof BP;Elemento O;Seidman JG;Seidman CE;Basson CT;Hatcher CJ
Holt-Oram综合征（HOS）是由TBX5基因突变引起的常染色体显性遗传心手综合征。在鸡前心外膜器官（PEO）中过表达Tbx5损害冠状血管形成。然而，Tbx5在心外膜本身的潜在活性，以及Tbx5在哺乳动物冠状动脉血管发生中的作用，在很大程度上仍然未知。评价Tbx5基因剂量改变对鸡胚和小鼠PEO和心外膜发育的影响。逆转录病毒介导的鸡胚PEO中Tbx5表达的敲低或上调以及胚胎小鼠中Tbx5的前心外膜特异性缺失（Tbx5epi −/）损害了正常PEO细胞发育，抑制了心外膜和冠状血管形成，并改变了发育基因表达。在胚胎第13.5 - 15.5天的突变心脏中，由于延迟的心外膜附着于心肌和EPDC的心外膜下积聚，心外膜衍生细胞（EPDC）的产生及其向心肌的迁移受到损害。这导致与血管平滑肌细胞募集受损相关的冠状动脉血管发生缺陷，并减少心脏成纤维细胞和内皮细胞侵入心肌的能力。与表现出复杂心室血管网络的野生型心脏相反，Tbx5epi −/−心脏显示出与心肌缺氧相关的血管密度显著降低，如HIF 1 α上调和Hypoxyprobe-1结合增加所示。与野生型小鼠相比，具有这种心肌缺氧的Tbx5epi −/−小鼠表现出运动能力降低。我们的研究结果支持保守的Tbx5剂量依赖性的要求，在鸡和小鼠冠状动脉血管形成的心外膜和心外膜祖细胞的发展。
Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ (PEO) impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and Tbx5’s role in mammalian coronary vasculogenesis, remains largely unknown. To evaluate the consequences of altered Tbx5 gene dosage during PEO and epicardial development in the embryonic chick and mouse. Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick PEO as well as proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5epi−/) impaired normal PEO cell development, inhibited epicardial and coronary blood vessel formation and altered developmental gene expression. The generation of epicardial-derived cells (EPDCs) and their migration into the myocardium was impaired between embryonic day (E) 13.5–15.5 in mutant hearts due to delayed epicardial attachment to the myocardium and subepicardial accumulation of EPDCs. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment, and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wildtype hearts that exhibited an elaborate ventricular vascular network, Tbx5epi−/− hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by HIF1α upregulation and increased binding of Hypoxyprobe-1. Tbx5epi−/− mice with such myocardial hypoxia exhibited reduced exercise capacity compared to wildtype mice. Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and mouse coronary vascular formation.