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J. Biol. Chem., Vol. 282, Issue 15, 11255-11265, April 13, 2007

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Arginine Vasopressin-mediated Cardiac Differentiation

INSIGHTS INTO THE ROLE OF ITS RECEPTORS AND NITRIC OXIDE SIGNALING^*

Natig Gassanov, Marek Jankowski, Bogdan Danalache, Donghao Wang, Ryszard Grygorczyk, Uta C. Hoppe, and Jolanta Gutkowska¹

From the Department of Internal Medicine III, University of Cologne, 50924 Cologne, Germany and the Research Center CHUM-Hotel-Dieu, University of Montreal, 3850 Saint-Urbain, Montreal, Quebec H2W 1T8, Canada

Despite the existence of a functional arginine vasopressin (AVP) system in the adult heart and evidence that AVP induces myogenesis, its significance in cardiomyogenesis is currently unknown. In the present study, we hypothesized a role for AVP in cardiac differentiation of D3 and lineage-specific embryonic stem (ES) cells expressing green fluorescent protein under the control of atrial natriuretic peptide (Anp) or myosin light chain-2V (Mlc-2V) promoters. Furthermore, we investigated the nitric oxide (NO) involvement in AVP-mediated pathways. AVP exposure increased the number of beating embryoid bodies, fluorescent cells, and expression of Gata-4 and other cardiac genes. V1a and V2 receptors (V1aR and V2R) differentially mediated these effects in transgenic ES cells, and exhibited a distinct developmentally regulated mRNA expression pattern. A NO synthase inhibitor, L-NAME, powerfully antagonized the AVP-induced effects on cardiogenic differentiation, implicating NO signaling in AVP-mediated pathways. Indeed, AVP elevated the mRNA and protein levels of endothelial NO synthase (eNOS) through V2R stimulation. Remarkably, increased beating activity was found in AVP-treated ES cells with down-regulated eNOS expression, indicating the significant involvement of additional pathways in cardiomyogenic effects of AVP. Finally, patch clamp recordings revealed specific AVP-induced changes of action potentials and increased L-type Ca²⁺ (I_Ca,L) current densities in differentiated ventricular phenotypes. Thus, AVP promotes cardiomyocyte differentiation of ES cells and involves Gata-4 and NO signaling. AVP-induced action potential prolongation appears likely to be linked to the increased I_Ca,L current in ventricular cells. In conclusion, this report provides new evidence for the essential role of the AVP system in ES cell-derived cardiomyogenesis.

Received for publication, November 20, 2006 , and in revised form, January 25, 2007.

^* This work was supported by grants from Deutsche Forschungsgemein-schaft (to N. G. and U. C. H.) and the Canadian Institutes of Health Research and the Canadian Heart and Stroke Foundation (to M. J. and J. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Pavillon Masson, 3850 Saint-Urbain, Montreal (QC) H2W 1T8, Canada. Tel.: 514-890-8000 (ext. 12731); Fax: 514-412-7204; E-mail: jolanta.gutkowska{at}umontreal.ca.

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