(H-291) Three-Dimensional Wall Shear Stress Characteristics in Rat Mesenteric Angiogenic Microvascular Networks Revealed Through Red Blood Cell-Resolved Modeling

Introduction:: Angiogenesis, the process of growing new blood vessels from existing vessels, is ubiquitous at all stages of animal life and in both health and disease. The process generally occurs in response to local stimuli, and predominant among these is the wall shear stress (WSS) exerted by flowing blood. Endothelial cells (ECs) line vessel walls and can sense and respond to external forces¹. 3D WSS characteristics experienced in angiogenic microvascular networks with complex surface topologies, however, are generally unknown. Recent work² demonstrated significant WSS variations due to both geometric vessel complexity and RBCs. Such findings drive our hypothesis that WSS behavior unique to angiogenesis may exist but requires high-resolution modeling to reveal. The objective of this work was to determine 3D WSS spatial characteristics in angiogenic microvascular networks by integrating high-fidelity simulation with real image data.

Materials and Methods:: RBC-resolved simulations were performed using a 3D immersed boundary method-based fluid dynamics solver³ which resolves flow and 3D RBCs with high fidelity. Blood is modeled as a suspension of 3D RBCs flowing with plasma, and the cells deform as they flow through the complex 3D microvessels. Each RBC is represented by an infinitesimally thin elastic membrane enclosing a viscous fluid representing hemoglobin. Angiogenic microvascular network imaging was performed on rat mesenteric tissues harvested post the stimulation of angiogenesis via 48-80 mast cell degranulation. Images shown in Figs. 1A,D were digitally reconstructed in 3D, and used to perform RBC-resolved simulations. Representative snapshots are shown in Figs. 1B,E.

Results, Conclusions, and Discussions:: Results: Output simulation data includes WSS values at 7 million wall points defining each network surface, resulting in detailed 3D WSS contours. Time averaged WSS (TAWSS) contours are shown in Figs. 1C,F for the two angiogenic networks. Significant WSS heterogenity is observed across vessels of different diameters and lengths. TAWSS values per vessel are shown in Fig. 1G versus diameter, with significant variations from 0.55 dyne/cm² to 132 dyne/cm². Within each vessel, the standard deviation of TAWSS spatial patterns averaged 7 dyne/cm², and reached 97 dyne/cm² in some vessels. To give further perspective on heterogeneity, a heatmap connecting vessel diameter and vessel length with TAWSS is presented on Fig. 1H. WSS values are all within a physiological range¹, and exhibit unique behavior influenced by angiogenic surface morphologies and RBCs.

Discussion: High fidelity 3D RBC resolved modeling has revealed 3D TAWSS patterns in angiogenic networks from the rat mesentery. Significant heterogeneity is predicted both from vessel to vessel, as well as within individual vessels on complex surfaces. Smaller capillaries incur larger variations, which decrease in larger diameter vessels. Within vessels, complex TAWSS patterns arise due to local surface morphologies unique to angiogenesis. Formation of TAWSS hot spots and cold spots in specific regions are shown to be enhanced by the presence of RBCs, and in some cases exist only when explicit RBCs are considered. Angiogenic vessel tortuosity further results in distinct TAWSS spatial patterns.

Conclusions: New findings from this work reveal significant WSS variations can occur in angiogenic microvascular networks at sub-EC length scales. The results provide a new characterization of the EC microenvironment during angiogenesis and provoke consideration of complex temporal and spatial profiles when probing EC responses in experiments. To our knowledge, no previous study has shown 3D TAWSS in angiogenic microvascular networks using RBC resolved simulation.


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References (Optional): : 1. Song et. al, PNAS, 2011. 2. Balogh et. al, Phys.Rep., 2019. 3. Balogh et. al, JCP., 2017.