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Competency of embryonic cardiomyocytes to undergo Purkinje fiber differentiation is regulated by endothelin receptor expression

Department of Cell Biology, Cornell University Medical College, 1300 York Avenue, New York, NY 10021, USA

*Author for correspondence (e-mail: tmikaw{at}med.cornell.edu)

Accepted 27 March 2002

Purkinje fibers of the cardiac conduction system differentiate from heart muscle cells during embryogenesis. In the avian heart, Purkinje fiber differentiation takes place along the endocardium and coronary arteries. To date, only the vascular cytokine endothelin (ET) has been demonstrated to induce embryonic cardiomyocytes to differentiate into Purkinje fibers. This ET-induced Purkinje fiber differentiation is mediated by binding of ET to its transmembrane receptors that are expressed by myocytes. Expression of ET converting enzyme 1, which produces a biologically active ET ligand, begins in cardiac endothelia, both arterial and endocardial, at initiation of conduction cell differentiation and continues throughout heart development. Yet, the ability of cardiomyocytes to convert their phenotype in response to ET declines as embryos mature. Therefore, the loss of responsiveness to the inductive signal appears not to be associated with the level of ET ligand in the heart. This study examines the role of ET receptors in this age-dependent loss of inductive responsiveness and the expression profiles of three different types of ET receptors, ET_A, ET_B and ET_B2, in the embryonic chick heart. Whole-mount in situ hybridization analyses revealed that ET_A was ubiquitously expressed in both ventricular and atrial myocardium during heart development, while ET_B was predominantly expressed in the atrium and the left ventricle. ET_B2 expression was detected in valve leaflets but not in the myocardium. RNase protection assays showed that ventricular expression of ET_A and ET_B increased until Purkinje fiber differentiation began. Importantly, the levels of both receptor isotypes decreased after this time. Retrovirus-mediated overexpression of ET_A in ventricular myocytes in which endogenous ET receptors had been downregulated, enhanced their responsiveness to ET, allowing them to differentiate into conduction cells. These results suggest that the developmentally regulated expression of ET receptors plays a crucial role in determining the competency of ventricular myocytes to respond to inductive ET signaling in the chick embryo.

Key words: Cardiac conduction system, Purkinje fibers, Endothelin receptor, Retrovirus, Embryonic chicken heart, Myocardium

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