Abstract
Shear stress induces directed endothelial cell (EC) migration in blood vessels leading to vessel diameter increase and induction of vascular maturation. Other factors, such as EC elongation and interaction between ECs and non-vascular areas are also important. Computational models have previously been used to study collective cell migration. These models can be used to predict EC migration and its effect on vascular remodelling during embryogenesis. We combined live time-lapse imaging of the remodelling vasculature of the quail embryo yolk sac with flow quantification using a combination of micro-Particle Image Velocimetry and computational fluid dynamics. We then used the flow and remodelling data to inform a model of EC migration during remodelling. To obtain the relation between shear stress and velocity in vitro for EC cells, we developed a flow chamber to assess how confluent sheets of ECs migrate in response to shear stress. Using these data as an input, we developed a multiphase, self-propelled particles (SPP) model where individual agents are driven to migrate based on the level of shear stress while maintaining appropriate spatial relationship to nearby agents. These agents elongate, interact with each other, and with avascular agents at each time-step of the model. We compared predicted vascular shape to real vascular shape after 4 hours from our time-lapse movies and performed sensitivity analysis on the various model parameters. Our model shows that shear stress has the largest effect on the remodelling process. Importantly, however, elongation played an especially important part in remodelling. This model provides a powerful tool to study the input of different biological processes on remodelling.
Highlights
Blood vessels are extremely adaptable and are able to quickly remodel in response to changing tissue demands
To achieve a better understanding of this process, we developed a computational model in which, shear stress mediated endothelial cell (EC) migration has the leading role and other factors, such as avascular regions and EC elongation, are accounted for
Vascular remodelling is known to be a compensatory mechanism during progression of some diseases such as vascular stenosis where, due to occlusion of a blood vessel, blood flow is redirected through small collateral vessels and outward remodelling of these vessels partially restores the blood flow to the hypoxic tissue [3, 6]
Summary
Blood vessels are extremely adaptable and are able to quickly remodel in response to changing tissue demands. Shear stress-driven pruning, contraction, and enlargement of vessel within a network was first introduced by Pries and Secomb [10] This idea was extended to propose vessel enlargement occurs as a result of migration of ECs from smaller, low flow vessels to contribute to the growth of enlarging higher flow vessels [9]. Based on this hypothesis, shear stress and the direction of flow promote migration of ECs, and the balance of these two factors contributes to remodelling of the vasculature during development
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