Hemodynamic-dependent patterning of endothelin converting enzyme 1 expression and differentiation of impulse-conducting Purkinje fibers in the embryonic heart

Abstract

Impulse-conducting Purkinje fibers differentiate from myocytes during embryogenesis. The conversion of contractile myocytes into conduction cells is induced by the stretch/pressure-induced factor, endothelin (ET). Active ET is produced via proteolytic processing from its precursor by ET-converting enzyme 1 (ECE1) and triggers signaling by binding to its receptors. In the embryonic chick heart, ET receptors are expressed by all myocytes, but ECE1 is predominantly expressed in endothelial cells of coronary arteries and endocardium along which Purkinje fiber recruitment from myocytes takes place. Furthermore, co-expression of exogenous ECE1 and ET-precursor in the embryonic heart is sufficient to ectopically convert cardiomyocytes into Purkinje fibers. Thus, localized expression of ECE1 defines the site of Purkinje fiber recruitment in embryonic myocardium. However, it is not known how ECE1 expression is regulated in the embryonic heart. The unique expression pattern of ECE1 in the embryonic heart suggests that blood flow-induced stress/stretch may play a role in patterning ECE1 expression and subsequent induction of Purkinje fiber differentiation. We show that gadolinium, an antagonist for stretch-activated cation channels, downregulates the expression of ECE1 and a conduction cell marker, Cx40, in ventricular chambers, concurrently with delayed maturation of a ventricular conduction pathway. Conversely,pressure-overload in the ventricle by conotruncal banding results in a significant expansion of endocardial ECE1 expression and Cx40-positive putative Purkinje fibers. Coincident with this, an excitation pattern typical of the mature heart is precociously established. These in vivo data suggest that biomechanical forces acting on, and created by, the cardiovascular system during embyogenesis play a crucial role in Purkinje fiber induction and patterning.

Epicardium‐derived cells are important for correct development of the Purkinje fibers in the avian heart

“…The recruitment of cardiomyocytes into the Purkinje fiber system has been demonstrated to be related to hemodynamic influences derived from the coronary vasculature and endocardial lining of the ventricular lumen Hyer et al, 1999), with mature ET-1 and the ECE1 metalloprotease as key inductive factors (Takebayashi-Suzuki et al, 2000;Reckova et al, 2003;Hall et al, 2004). Earlier work demonstrated dramatic effects on the development of cardiac architecture and coronary vasculature when epicardial differentiation was disturbed (Gittenberger-de Groot et al, 2000;Tevosian et al, 2000;Lie-Venema et al, 2003;Eralp et al, 2005).…”

“…These unique differentiation sites suggested an inductive role both for periarterial and subendocardial EPDCs and for a paracrine signal from the endocardium and arterial beds in the recruitment of cardiomyocytes into the Purkinje fiber network (Gittenberger-de Groot et al, 2003b;Gourdie et al, 2003). Recent experimentation showed that Purkinje fiber differentiation is tightly regulated by hemodynamic alterations, while mature endothelin-1 (ET-1) and ET-converting enzyme 1 (ECE1) were identified as inductive molecules (Takebayashi-Suzuki et al, 2000;Reckova et al, 2003;Hall et al, 2004). Concomitant retroviral expression of mature ET-1 and ECE1 was even sufficient for the ectopic conversion of adjacent cardiomyocytes into Purkinje fibers (Takebayashi-Suzuki et al, 2000).…”

Zebrafish IRX1b in the embryonic cardiac ventricle

“…The specialized conduction system of the vertebrate ventricle has been demonstrated to arise from nonspecialized myocytes in a process involving induction by endothelin acting in concert with a locally expressed endothelin converting enzyme (Gourdie et al, 1998;Hyer et al, 1999;Hall et al, 2004). Dysfunction of the specialized cardiac conduction system or the normal patterns of intraventricular depolarization by a wide range of inherited and acquired pathological conditions can result in ventricular arrhythmias and sudden cardiac death (Wenink, 1979).…”

Iroquois homeobox gene 3 establishes fast conduction in the cardiac His–Purkinje network

“…At the cellular level, efficient impulse propagation through this network is dependent upon the interplay between cell morphology, membrane excitability, and electrical coupling of adjacent cells via gap junctions, the latter of which is the major determinant for rapid and directional conduction (3). Although regulation of early VCS specification and morphogenesis is becoming well understood (4)(5)(6)(7)(8)(9), less is known about how cells of the VCS gain their specialized conduction properties as they mature.…”