Deficient signaling via Alk2 (Acvr1) leads to bicuspid aortic valve development.
Deficient signaling via Alk2 (Acvr1) leads to bicuspid aortic valve development.
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DOI：
10.1371/journal.pone.0035539
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kaartinen V
中科院分区：
文献类型：
--
作者：
Thomas PS;Sridurongrit S;Ruiz-Lozano P;Kaartinen V
二叶式主动脉瓣（BAV）是人类最常见的先天性心脏异常。尽管最近取得了进展，但 BAV 发展的分子基础仍知之甚少。此前已有研究表明，Notch1 基因突变会导致人和小鼠的 BAV 和瓣膜钙化，而缺乏 Gata5 或其下游靶标 Nos3 的小鼠已被证明会表现出 BAV。在这里，我们发现，垫间充质中编码 I 型激活素受体（Alk2 或 Acvr1）的基因的组织特异性缺失会导致包括 BAV 在内的主动脉瓣缺陷的形成。这些缺陷主要是由于流出道中胚胎主动脉瓣叶前体垫的正常发育失败，导致右侧和非冠状动脉小叶融合，或者仅存在非常小的、发育不全的非冠状动脉小叶。幸存的成年突变小鼠表现出高频率的主动脉瓣狭窄和偶尔的主动脉瓣关闭不全。此类动物中增厚的主动脉瓣叶并未表现出 Bmp 信号传导活性的变化，而 Map 激酶途径则被激活。尽管功能障碍与基因表达中的一些促成骨差异相关，但在具有狭窄的 Alk2 突变体的主动脉瓣中未检测到钙化或炎症。我们的结论是，通过 Alk2 发出的信号对于子宫内主动脉瓣的适当发育是必需的，并且该过程中的缺陷会导致以后生活中的间接继发并发症。
Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly in humans. Despite recent advances, the molecular basis of BAV development is poorly understood. Previously it has been shown that mutations in the Notch1 gene lead to BAV and valve calcification both in human and mice, and mice deficient in Gata5 or its downstream target Nos3 have been shown to display BAVs. Here we show that tissue-specific deletion of the gene encoding Activin Receptor Type I (Alk2 or Acvr1) in the cushion mesenchyme results in formation of aortic valve defects including BAV. These defects are largely due to a failure of normal development of the embryonic aortic valve leaflet precursor cushions in the outflow tract resulting in either a fused right- and non-coronary leaflet, or the presence of only a very small, rudimentary non-coronary leaflet. The surviving adult mutant mice display aortic stenosis with high frequency and occasional aortic valve insufficiency. The thickened aortic valve leaflets in such animals do not show changes in Bmp signaling activity, while Map kinase pathways are activated. Although dysfunction correlated with some pro-osteogenic differences in gene expression, neither calcification nor inflammation were detected in aortic valves of Alk2 mutants with stenosis. We conclude that signaling via Alk2 is required for appropriate aortic valve development in utero, and that defects in this process lead to indirect secondary complications later in life.
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影响因子：
2.7
作者：
Dupuis LE;McCulloch DR;McGarity JD;Bahan A;Wessels A;Weber D;Diminich AM;Nelson CM;Apte SS;Kern CB
通讯作者：
Kern CB
影响因子：
20.1
作者：
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通讯作者：
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影响因子：
24
作者：
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通讯作者：
Sans-Coma, Valentin
影响因子：
10.8
作者：
Gan, LM;Selin-Sjögren, L;Jern, S
通讯作者：
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影响因子：
64.8
作者：
Garg, V;Muth, AN;Srivastava, D
通讯作者：
Srivastava, D