While the embryonic heart is developing and maturing towards its four-chambered form, the cardiac conduction system (CCS) is developing as well. The CCS will provide the heart with the required... Show moreWhile the embryonic heart is developing and maturing towards its four-chambered form, the cardiac conduction system (CCS) is developing as well. The CCS will provide the heart with the required wiring system to ensure the properly orchestrated contraction of the myocardial chambers. In both the young and adult population rhythm disturbances or cardiac arrhythmias can occur. Electrophysiological studies have shown that these events do not occur randomly in the heart but rather at anatomical predilection sites. This thesis presents our results on the morphological as well as electrophysiological changes that occur during heart development, specifically in the developing sinoatrial and atrioventricular node. By studying the developmental changes we aim to increase our knowledge on the mechanism underlying arrhythmias. Show less
The processes of heart development, in which a primitive heart tube transforms into a specialized organ with two atria and ventricles divided by septa, are not only important for the understanding... Show moreThe processes of heart development, in which a primitive heart tube transforms into a specialized organ with two atria and ventricles divided by septa, are not only important for the understanding of congenital heart defects. These processes also give more insight for the development of heart regeneration therapies. The aim of this thesis was two fold. In the first part, we described the expression pattern of PDGF-A, -C and their receptor PDGFR-_ in the avian heart. Additionally, we studied mouse embryos in which the Pdgfr_ gene was mutated. These data show new insights into the role of PDGFR in a gene regulatory network which supports the development of cardiac structures. The second part of this thesis focused on the process of EMT in human adult EPDC and the role of the EPDC in the differentiation of cardiomyocytes. We gained more insight into the factors involved in EMT of the adult epicardium and showed that EPDCs are indispensible for proper integration of cardiomyocytes into a synchronously beating syncythium. These results might be beneficial for endogenous regulated cell-based cardiac repair. Show less
This thesis introduces the posterior heart field contributing to the venous pole of the heart by epithelial-mesenchymal-transformation of the coelomic epithelium. Based on studying of podoplanin... Show moreThis thesis introduces the posterior heart field contributing to the venous pole of the heart by epithelial-mesenchymal-transformation of the coelomic epithelium. Based on studying of podoplanin and Sp3 (novel genes in cardiogenesis) wildtype and knockout mouse embryos between stages 9.5-18.5, we postulate that the posterior heart field contributes through mesenchymal and myocardial cell populations. The mesenchymal population is involved in the formation of the proepicardial organ, epicardium and epicardium-derived cells. The hypoplastic proepicardial organ and impaired epicardial-myocardial interaction result from altered mesenchymal contribution of the posterior heart field by lack of podoplanin and SP3 leading to hypoplasia of the chamber myocardium and coronary arterial vascular wall as well as (atrioventricular) septal defects. Myocardial contribution concerns myocardium of the sinus venosus including the sinoatrial node, venous valves, primary atrial septum and the left atrial dorsal wall as well as the wall of the pulmonary and cardinal veins. Development of smooth-muscle-cells of the wall of the pulmonary vein is also related to the posterior heart field. Moreover, we have reported formation of a transient left-sided sinoatrial node which persists during development in 10% of the cases. Podoplanin mutants show cardiac malformations including a hypoplastic sinoatrial node. This thesis contributes to the understanding of the mechanism underlying the mentioned cardiac malformations and arrhythmias originating in the sinus venosus region. Show less
The central cell type within vascular development is the endothelial cell (EC). It forms during (lymph)vasculogenesis, proliferates during angiogenesis and instructs medial cells during... Show moreThe central cell type within vascular development is the endothelial cell (EC). It forms during (lymph)vasculogenesis, proliferates during angiogenesis and instructs medial cells during arteriogenesis. The venous population also gives rise to a subset of the lymphatic endothelium and the endocardium is instructive in formation of the primitive heart. We show that endothelial plasticity is very high in the developing embryo/fetus and that its outcome is dependent on the VEGF, Notch and PDGF-signaling pathways. Alterations in VEGF and Notch-signaling abrogate endocardial and endothelial differentiation, cardiac development and coronary maturation. Alterations in these pathways are most likely also involved in abnormal lymphatic development as seen in fetuses with increased nuchal translucency. In this thesis, lymphatic endothelial plasticity is particularly underscored, as lymphatic ECs gain arterial characteristics in certain pathological situations. Additionally, we show that impaired VEGF, Notch and PDGF-B/PDGFR-_-signaling in ECs and/or vSMCs severely impairs coronary arteriogenesis. In conclusion, many growth factors either influencing the EC (such as VEGF) or produced by the EC (such as PDGF) play a role in regulating and fine-tuning these processes. Increasing our knowledge on how these factors influence (ab)normal vascular development will improve our understanding of many pathological conditions and might increase therapeutic approaches. Show less
