Hemodynamics in Cardiac Development

Abstract

The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular as yet unsegmented heart. With development, the looping heart becomes asymmetric providing varying diameters and curvatures resulting in unequal flow profiles. These flow profiles exert various wall shear stresses and as a consequence different expression patterns of shear responsive genes. In this paper we investigate the morphological alterations of the heart after changing the blood flow by ligation of the right vitelline vein in a model chicken embryo and analyze the extended expression in the endocardial cushions of the shear responsive gene Tgfbeta receptor III. A major phenomenon is the diminished endocardial-mesenchymal transition resulting in hypoplastic (even absence of) atrioventricular and outflow tract endocardial cushions, which might be lethal in early phases. The surviving embryos exhibit several cardiac malformations including ventricular septal defects and malformed semilunar valves related to abnormal development of the aortopulmonary septal complex and the enclosed neural crest cells. We discuss the results in the light of the interactions between several shear stress responsive signaling pathways including an extended review of the involved Vegf, Notch, Pdgf, Klf2, eNos, Endothelin and Tgfβ/Bmp/Smad networks.

Development and evolution of the metazoan heart

“…Heterospecific interactions between a small number of the transcription factors Tbx5 and Nkx2.5, and GATA4, also part of the cardiogenic tool kit, underlying gene expression patterns in specific tissues, have been demonstrated in mammalian cardiogenesis . However, this shows much complexity and requires fine‐tuning involving additional partners, including histone modifications, epigenetic regulation, involvement of hemodynamics, regulation of cell movement, and participation of microRNAs to provide for expansion of cardiac progenitors, compartments, and cell differentiation.…”

“…Each individual cushion probably receives its own balanced set of mesenchymal cells . In chicken embryos, it is shown that the formation of the semilunar valves highly depends on the interaction of endocardial and NC‐derived mesenchymal cells guided by hemodynamical forces sculpting the OFT . It is noteworthy that also in these events of cardiogenesis, asymmetric development is apparent, although the main leaflets of the aortic and pulmonary semilunar valves originate from the same two OFT endocardial cushions.…”

“…1 The prenatal demise is unknown, but in a series of early studies encompassing knockouts in mice, an estimated 50% of prenatal lethality is due to malfunctioning of the cardiovascular and/or hemopoietic system. 6 It is evident that the myriad phenotypes of congenital human malformations must not be considered as interrupted or persisting steps in the evolution of the heart, but rather as results of mutations, imbalance in dosage, or "mismanagement" in the available (genetic) tool kits, including epigenetic regulation, 211 hemodynamics, 67,212 and external factors such as vitamin A/retinoic acid. 56,213 The complexity of interactions leading to CHD may be inferred from large cohort studies in which mutations of many genes 214 and parts of epigenetic pathways 66 are involved.…”

The Development of the Ascending Aortic Wall in Tricuspid and Bicuspid Aortic Valve: A Process from Maturation to Degeneration

“…The morphogenetic processes underlying the differences in the structure of the elastic arteries [5] and the muscular arteries are still poorly understood. Most probably, these are the results of origin of the endothelial and the VSMC populations in combination with the role of hemodynamics [7]. The great arteries in general are more influenced by high shear stress and pressure.…”

Optical coherence tomography for in vivo imaging of endocardial to mesenchymal transition during avian heart development

“…Many studies have been performed in order to discover the genetic and molecular signaling pathways involved in EndMT, e.g., [18,19,20,21,22]. Several studies have also pointed to flow-mediated signaling pathways as key drivers of EndMT, e.g., [23,24,25,26,27,28,29,30]. In particular, altered hemodynamics are known to cause congenital heart defects, and it is therefore desirable to understand in more detail how perturbations in flow affect EndMT such that valve and septa formation are disrupted.…”