The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression.
The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression.
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DOI：
10.1016/j.devcel.2014.12.009
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发表时间：
2015-01-26
影响因子：
11.8
通讯作者：
Kahn ML
中科院分区：
文献类型：
--
作者：
Zhou Z;Rawnsley DR;Goddard LM;Pan W;Cao XJ;Jakus Z;Zheng H;Yang J;Arthur JS;Whitehead KJ;Li D;Zhou B;Garcia BA;Zheng X;Kahn ML
脑海绵状血管畸形（CCM）通路是正常心血管发育和预防出生后血管畸形所需的内皮细胞，但其分子效应子尚未明确。在这里，我们表明，在内皮细胞的CCM信号的损失导致妊娠中期心力衰竭与心脏胶质的过早降解。CCM缺陷显著改变内皮细胞和内皮基因表达，包括Klf2和Klf4转录因子以及降解心胶的Adamts4和Adamts5蛋白酶的表达增加。这些基因表达的变化是由于MEKK3活性增加所致，MEKK3是一种与内皮细胞中的CCM 2结合的促分裂原活化蛋白激酶。MEKK3对于这些基因的表达是必要的和足够的，并且MEKK3的部分缺失挽救了CCM缺陷胚胎中的心脏缺陷。这些发现揭示了CCM信号在心血管发育过程中控制内皮基因表达的分子机制，这也可能是CCM形成的基础。
The cerebral cavernous malformation (CCM) pathway is required in endothelial cells for normal cardiovascular development and to prevent postnatal vascular malformations, but its molecular effectors are not well defined. Here we show that loss of CCM signaling in endocardial cells results in mid-gestation heart failure associated with premature degradation of cardiac jelly. CCM deficiency dramatically alters endocardial and endothelial gene expression, including increased expression of the Klf2 and Klf4 transcription factors and the Adamts4 and Adamts5 proteases that degrade cardiac jelly. These changes in gene expression result from increased activity of MEKK3, a mitogen-activated protein kinase that binds CCM2 in endothelial cells. MEKK3 is both necessary and sufficient for expression of these genes, and partial loss of MEKK3 rescues cardiac defects in CCM-deficient embryos. These findings reveal a molecular mechanism by which CCM signaling controls endothelial gene expression during cardiovascular development that may also underlie CCM formation.