Critical Transitions in Early Embryonic Aortic Arch Patterning and Hemodynamics

Abstract

Transformation from the bilaterally symmetric embryonic aortic arches to the mature great vessels is a complex morphogenetic process, requiring both vasculogenic and angiogenic mechanisms. Early aortic arch development occurs simultaneously with rapid changes in pulsatile blood flow, ventricular function, and downstream impedance in both invertebrate and vertebrate species. These dynamic biomechanical environmental landscapes provide critical epigenetic cues for vascular growth and remodeling. In our previous work, we examined hemodynamic loading and aortic arch growth in the chick embryo at Hamburger-Hamilton stages 18 and 24. We provided the first quantitative correlation between wall shear stress (WSS) and aortic arch diameter in the developing embryo, and observed that these two stages contained different aortic arch patterns with no inter-embryo variation. In the present study, we investigate these biomechanical events in the intermediate stage 21 to determine insights into this critical transition. We performed fluorescent dye microinjections to identify aortic arch patterns and measured diameters using both injection recordings and high-resolution optical coherence tomography. Flow and WSS were quantified with 3D computational fluid dynamics (CFD). Dye injections revealed that the transition in aortic arch pattern is not a uniform process and multiple configurations were documented at stage 21. CFD analysis showed that WSS is substantially elevated compared to both the previous (stage 18) and subsequent (stage 24) developmental time-points. These results demonstrate that acute increases in WSS are followed by a period of vascular remodeling to restore normative hemodynamic loading. Fluctuations in blood flow are one possible mechanism that impacts the timing of events such as aortic arch regression and generation, leading to the variable configurations at stage 21. Aortic arch variations noted during normal rapid vascular remodeling at stage 21 identify a temporal window of increased vulnerability to aberrant aortic arch morphogenesis with the potential for profound effects on subsequent cardiovascular morphogenesis.

Congenital heart malformations induced by hemodynamic altering surgical interventions

“…The fifth arch pair have been have been termed to describe arteries that are only temporarily present in early development of the chick embryo, and are not considered a major PAA (Hiruma and Hirakow, 1995). Proper arch formation depends on programmed processes but is also regulated by blood flow conditions (Keller et al, 2007; Pekkan et al, 2008; Kowalski et al, 2013). …”

“…To this end, research that integrates hemodynamic data with biological change in response to hemodynamics, and the mechanisms behind this response, are essential. Several studies to determine hemodynamics in the developing embryonic heart are have been recently published (McQuinn et al, 2007; Stekelenburg-De Vos et al, 2007; Liu et al, 2012; Kowalski et al, 2013; Shi et al, 2013), as well as studies to look at remodeling and changes in tissue properties shortly after interventions and flow exposure (Groenendijk et al, 2007; Biechler et al, 2010; Yalcin et al, 2011; Buskohl et al, 2012; Tan et al, 2013). As these two aspects of cardiac development are put together, a more complete picture of heart formation is emerging where developmental programming plays a substantial role, which needs to be better characterized and studied.…”

Cardio-respiratory development in bird embryos: new insights from a venerable animal model

“…This allows the experimenter to modulate the embryonic environment during growth (e.g., inducing hypoxia at controlled levels). When these two attributes are combined with the relatively large size of the embryos of some avian species, it becomes apparent that avian embryos have allowed invasive experimental manipulations (Burggren et al, 2004;Kowalski et al, 2013;Shell et al, 2016). Such invasive procedures have primarily focused on the embryo of the chicken but also the embryos of other birds such as the emu (Dromaius novaehollandiae) and ostrich (Struthio camelus).…”

Growth and hemodynamics after early embryonic aortic arch occlusion

“…Changes in WSS patterns are detected through endothelial cells, which convert mechanical stimuli into intracellular signals, leading to an increase or decrease in vessel diameter (Bayer et al, 1999; Girerd et al, 1996; Langille and O’Donnell, 1986). Recent studies of the Hamburger-Hamilton (HH) stage 18, 21, and 24 PAA have revealed clear relationships between PAA flow, WSS, and luminal growth (Kowalski et al, 2013; Wang et al, 2009). While the asymmetric PAA regression pattern has been shown to occur by differential apoptosis (Molin et al, 2002), the expression of genes that normally orchestrate left/right asymmetry has not been observed in the PAA (Liu et al, 2002; Yashiro et al, 2007).…”