Journal
CIRCULATION RESEARCH
Volume 102, Issue 5, Pages 615-623Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.160861
Keywords
Vangl2; planar cell polarity; cardiac development; myocardium; coronary vasculature
Funding
- British Heart Foundation [BS/05/003, PG/05/041] Funding Source: Medline
- Medical Research Council [G120/861, MC_UP_1502/1] Funding Source: Medline
- Medical Research Council [MC_UP_1502/1, G120/861] Funding Source: researchfish
- MRC [MC_UP_1502/1, G120/861] Funding Source: UKRI
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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-cellautonomous effects on the formation of the coronary vasculature.
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