Phillips Helen M, Hildreth Victoria, Peat Jonathan D, Murdoch Jennifer N, Kobayashi Kazuto, Chaudhry Bill, Henderson Deborah J
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, NE1 3BZ, United Kingdom.
Circ Res. 2008 Mar 14;102(5):615-23. doi: 10.1161/CIRCRESAHA.107.160861. Epub 2008 Jan 3.
Establishment of cellular polarity is essential for the development of many tissues. In this study, we describe defects in the formation of the coronary vasculature in the loop-tail (Lp) mutant in which the planar cell polarity (PCP) gene, Vangl2, is disrupted. Although Vangl2 is expressed exclusively in the myocardial cells of the developing heart, the coronary vessels do not develop an intact smooth muscle layer, and there are enlarged, ectopic vessels on the surface of the heart. Reduced fibronectin deposition in the subepicardial space is associated with limited migration of epicardially derived cells (EPDCs) into the ventricular myocardium and likely contributes to these defects. Analysis of cardiomyocytes shows that the actin cytoskeleton is disrupted and the cytoarchitecture of the ventricular myocardium is abnormal in Lp/Lp hearts. Moreover, activation of RhoA/Rho kinase signaling is disrupted in these cells. Conditional inhibition of myocardial Rho kinase activity disrupts the organization of the cardiomyocytes and formation of the coronary vessels to produce the same spectrum of defects as seen in Lp. These data suggest that Vangl2 and Rho kinase act cell autonomously in the myocardium to regulate the organization of cardiomyocytes but also have non-cell-autonomous effects on the formation of the coronary vasculature.
细胞极性的建立对许多组织的发育至关重要。在本研究中，我们描述了环形尾巴（Lp）突变体中冠状血管形成的缺陷，该突变体中平面细胞极性（PCP）基因Vangl2被破坏。尽管Vangl2仅在发育中心脏的心肌细胞中表达，但冠状血管并未发育出完整的平滑肌层，并且心脏表面存在扩大的异位血管。心外膜下空间中纤连蛋白沉积减少与心外膜来源细胞（EPDC）向心室心肌的迁移受限有关，并且可能导致了这些缺陷。对心肌细胞的分析表明，Lp/Lp心脏中的肌动蛋白细胞骨架被破坏，心室心肌的细胞结构异常。此外，这些细胞中RhoA/Rho激酶信号的激活被破坏。心肌Rho激酶活性的条件性抑制会破坏心肌细胞的组织和冠状血管的形成，从而产生与Lp中所见相同范围的缺陷。这些数据表明，Vangl2和Rho激酶在心肌中自主发挥作用，以调节心肌细胞的组织，但对冠状血管的形成也有非细胞自主效应。
