Published online before print January 3, 2008, doi: 10.1161/CIRCRESAHA.107.160861
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Submitted on February 19, 2007
Revised on December 19, 2007
Accepted on December 21, 2007
Non–Cell-Autonomous Roles for the Planar Cell Polarity Gene Vangl2 in Development of the Coronary Circulation
Helen M. Phillips ;
From the Institute of Human Genetics (H.M.P., V.H., J.D.P., B.C., D.J.H.), Newcastle University, Newcastle upon Tyne, UK; Medical Research Center Mammalian Genetics Unit (J.N.M.), Harwell, Oxon, UK; and Department of Molecular Genetics (K.K.), Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan.
* To whom correspondence should be addressed. E-mail: d.j.henderson{at}ncl.ac.uk.
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.
Key words: Vangl2 • planar cell polarity • cardiac development • myocardium • coronary vasculature
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