- Award ID(s):
- 1828163
- NSF-PAR ID:
- 10106513
- Date Published:
- Journal Name:
- Journal of Cardiovascular Development and Disease
- Volume:
- 6
- Issue:
- 1
- ISSN:
- 2308-3425
- Page Range / eLocation ID:
- 6
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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null (Ed.)Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24 hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.more » « less
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Abstract Background While much is known about the genetic regulation of early valvular morphogenesis, mechanisms governing fetal valvular growth and remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Side‐specific activity of valvulogenic programs motivates the hypothesis that shear stress pattern‐specific endocardial signaling controls the elongation of leaflets.
Results We determined that extension of the semilunar valve occurs via fibrosa sided endocardial proliferation. Low OSS was necessary and sufficient to induce canonical Wnt/β‐catenin activation in fetal valve endothelium, which in turn drives BMP receptor/ligand expression, and pSmad1/5 activity essential for endocardial proliferation. In contrast, ventricularis endocardial cells expressed active Notch1 but minimal pSmad1/5. Endocardial monolayers exposed to LSS attenuate Wnt signaling in a Notch1 dependent manner.
Conclusions Low OSS is transduced by endocardial cells into canonical Wnt signaling programs that regulate BMP signaling and endocardial proliferation. In contrast, high LSS induces Notch signaling in endocardial cells, inhibiting Wnt signaling and thereby restricting growth on the ventricular surface. Our results identify a novel mechanically regulated molecular switch, whereby fluid shear stress drives the growth of valve endothelium, orchestrating the extension of the valve in the direction of blood flow.
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Within developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extending
Drosophila germband epithelium, which displays planar-polarized myosin II and experiences anisotropic forces from neighboring tissues. We show that, in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues, two experimentally accessible metrics of cell patterns—the cell shape index and a cell alignment index—are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in theDrosophila germband predict the onset of rapid cell rearrangement in both wild-type andsnail twist mutant embryos, where our theoretical prediction is further improved when we also account for cell packing disorder. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue-shape changes during rapid developmental events. -
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ABSTRACT Early outflow morphogenesis is a critical event in cardiac development. Understanding mechanical and molecular based morphogenetic relationships at early stages of cardiogenesis is essential for the advancement of cardiovascular technology related to congenital heart defects. In this study, we pair molecular changes in pharyngeal arch artery (PAA) vascular smooth muscle cells (VSMCs) with hemodynamic changes over the course of the same period. We focus on Hamburger Hamilton stage 24–36 chick embryos, using both Doppler ultrasound and histological sections to phenotype PAA VSMCs, and establish a relationship between hemodynamics and PAA composition. Our findings show that PAA VSMCs transition through a synthetic, intermediate, and contractile phenotype over time. Wall shear stress magnitude per arch varies throughout development. Despite distinct hemodynamic and fractional expression trends, no strong correlation was found between the two, indicating that WSS magnitude is not the main driver of PAA wall remodeling and maturation. While WSS magnitude was not found to be a major driver, this work provides a basic framework for investigating relationships between hemodynamic forces and tunica media during a critical period of development. Anat Rec, 302:153–162, 2019. © 2018 Wiley Periodicals, Inc.