ABSTRACT:The developing sinus venosus myocardium, derived from the posterior heart field, contributes to the atrial septum, the posterior atrial wall, the sino-atrial node, and myocardium lining the pulmonary and cardinal veins, all expressing podoplanin, a coelomic and myocardial marker. We compared development and differentiation of the myocardium and vascular wall of the pulmonary veins (PV), left atrial dorsal wall, and atrial septum in wild type with podoplanin knockout mouse embryos (E10.5-E18.5) by 3D reconstruction and immunohistochemistry. Expression of Nkx2.5 in the pulmonary venous myocardium changes from mosaic to positive during development pointing out a high proliferative rate compared with Nkx2.5 negative myocardium of the sino-atrial node and cardinal veins. In mutants, myocardium of the PVs, dorsal atrial wall and atrial septum was hypoplastic. The atrial septum and right-sided wall of the PV almost lacked interposed mesenchyme. Extension of smooth muscle cells into the left atrial body was diminished. We conclude that myocardium of the PVs, dorsal atrial wall, and atrial septum, as well as the smooth muscle cells, are derived from the posterior heart field regulated by podoplanin. (Pediatr Res 65: 27-32, 2009) T he developmental origin and molecular mechanisms controlling the formation of the myocardium of the pulmonary veins (PV) and the smooth muscle cells (SMCs) of the PV media are a matter of debate. The PV myocardial sleeve develops by either migration of myocardial cells from the left atrium (LA) (1) or by recruitment of extracardiac mesenchymal cells, which differentiate into myocardial cells (2). Based on expression patterns of Nkx2.5, Islet1, and Pitx2c the LA and PV myocardium was suggested to be formed by the addition of myocardial cells from the second heart field at the venous pole (3).The second heart field, part of the splanchnic mesoderm, is involved in the addition of (myocardial) cells to the primary heart tube at both the arterial (the secondary and anterior heart field) and the venous pole (the posterior heart field) (4). Islet1, a marker of undifferentiated cardiac progenitor cells, is expressed throughout the second heart field (5). Myocardial cells can differentiate from second heart field derived mesenchymal cells, and SMCs may also differentiate from mesenchyme (6).The transmembrane glycoprotein podoplanin, a coelomic and myocardial marker expressed in the posterior heart field (7), has gained interest for its role in epithelial-tomesenchymal transformation (EMT) and in formation of the myocardium and coronary SMCs at the venous pole of the heart (8). It is found in the proepicardial organ, epicardium, and sinus venosus myocardium including the sino-atrial node, the PVs and cardinal veins, the dorsal atrial wall and the base of the atrial septum extending into the developing atrial and ventricular cardiac conduction system. Podoplanin promotes EMT by binding ezrin, radixin, moesin (ERM) proteins that activate RhoA, and by down-regulation of the cell-to-cell adhesion mo...
