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.
Highlights
Heart development requires complex interactions starting with the mesodermal cardiac crescent and resulting in birds and mammals in the fully septated four-chambered beating heart
After ligation the inner curvature was wider creating a larger distance between outflow tract (OFT) and AV area
In vitro neural crest (NC) cells produce a latent form of Tgfß [38], abundantly present in the matrix of embryonic hearts [39] that could be activated by NC proteolysis, and is diminished after venous ligation because of a diminished apoptosis
Summary
Heart development requires complex interactions starting with the mesodermal cardiac crescent and resulting in birds and mammals in the fully septated four-chambered beating heart. Besides being influenced by hemodynamics, genes might be caught in webs of other interactions exemplified by the Sonic hedgehog (Shh)–Gli pathway, that is shear stress dependent being part of the shear-sensing primary cilium [15], and involved in cholesterol metabolism [16] To carry this even further interactions between Shh–Gli with Zic, Pitx and Nodal are important in left–right asymmetry [17] while Nodal–Pitx interactions are involved in asymmetrical development of the pharyngeal arch arteries. We will blend the results of shear stress sensitivity on changes in gene expression patterns in a broader sense including a literature review of the involvement of essential shear stress-responsive gene networks in cardiac development, as brought to us by several different approaches These include: (i) cell culture systems, (ii) in vivo transgenic technology, (iii) the survey of (cardiovascular) patient populations and (iv) direct (surgical) manipulations in chicken embryos
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