Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan; Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Cell Rep. 2018 May 22;23(8):2455-2466. doi: 10.1016/j.celrep.2018.04.080.
The four-chamber structure of the mammalian heart is established during embryonic development. While key regulators for ventricular development are well studied, regulatory mechanisms for atrial chamber morphogenesis remain poorly understood. Here, we found that angiopoietin-1 (Angpt1), a vascular maturation factor, is highly and specifically expressed in atrial myocardium during heart development. Loss of myocardial Angpt1 in mouse embryo led to severe impairment in atrial chamber morphogenesis. We revealed that Angpt1 deficiency results in excessive deposition of cardiac jelly, which disturbs regulation of myocardial growth, thereby impairing maturation of atrial chambers. Mechanistically, myocardial Angpt1 activates endocardial Tie2 and positively regulates expression of ADAMTS proteases, which is crucial for proper degradation of cardiac jelly. Accordingly, loss of Tie2 also impairs ADAMTS-mediated degradation of cardiac jelly in atrium. Collectively, myocardial Angpt1/endocardial Tie2 signaling in atrium promotes spatiotemporal degradation of cardiac jelly during early cardiac development and is therefore indispensable for atrial chamber morphogenesis.
哺乳动物心脏的四腔结构是在胚胎发育过程中建立的。虽然心室发育的关键调节因子已得到充分研究，但心房室形态发生的调节机制仍知之甚少。在这里，我们发现血管成熟因子血管生成素 1 (Angpt1) 在心脏发育过程中高度且特异性地表达于心房心肌中。在小鼠胚胎中敲除心肌 Angpt1 导致心房室形态发生严重受损。我们揭示了 Angpt1 缺乏导致心脏果冻的过度沉积，扰乱了心肌生长的调节，从而损害了心房的成熟。在机制上，心肌 Angpt1 激活心内膜 Tie2 并正向调节 ADAMTS 蛋白酶的表达，这对于心脏果冻的适当降解至关重要。因此，Tie2 的缺失也会损害心房中 ADAMTS 介导的心脏果冻降解。总之，心房中的心肌 Angpt1/心内膜 Tie2 信号促进了早期心脏发育过程中心脏果冻的时空降解，因此对于心房室形态发生是必不可少的。
