K14 - Revealing Hemodynamic Characteristics of New Blood Vessel Sprouts Using High-Fidelity Red Blood Cell Resolved Simulations

Introduction: : The sprouting of new blood vessels off existing vessels, or sprouting angiogenesis, is ubiquitous at all stages of animal life and in both health and disease. Endothelial cells (ECs) lining the blood vessels move/reorganize in response to local stimuli in the host vessel, such as wall shear stress (WSS) exerted by blood, to form new vessel sprouts that are blind-ended and extremely leaky. While it has long been known that hemodynamics influences sprout growth, current knowledge is based on idealized geometries and reduced-order approaches that fail to capture the 3D details and RBC dynamics present in vivo. As a result, important questions remain, such as: What are the effects of unsteady RBC flow in the host vessel? Do RBCs entering the sprout lumen have any significant impact on sprout hemodynamics? Previous work has shown significant time dependent changes of hemodynamics due to the unsteady flow of RBCs though for matured vessels, which drives our hypothesis that unique time dependent and time averaged hemodynamic characteristics exist in vessel sprouts. Revealing such characteristics and answering the above questions require 3D RBC resolved simulations in real sprout geometry. The objective of this work is to model in vivo microvessel sprouts off host vessels using high-fidelity simulations, resolving 3D EC surfaces and physiological permeability of leaky sprouts.

Materials and

Methods: : High fidelity RBC resolved simulations were performed using a 3D immersed boundary method (IBM) based fluid dynamic solver(1). 3D sprouts were constructed based on the imaging of rat mesenteric microvascular sprouts observed during angiogenic remodeling. For the base case, the host vessel has a diameter of 20 µm, while the sprout has variable diameters along the sprout length. Individual ECs comprising the sprout walls and representative EC gaps were constructed matching the physiological permeability of leaky sprouts. Simulations were performed for two different permeabilities (high and regular), range of shear rates (SR), host vessel diameter and overall hematocrit levels (Ht). Output simulation data are used to quantify key hemodynamic features such as time dependent and time averaged wall shear stress (WSS) along the sprout, leakage flux etc.

Results, Conclusions, and Discussions:: Results & Discussions:
The findings show that the unsteady movement of RBCs inside the host vessel induces physiologically significant, time-dependent WSS variations along the length of the sprout, which are affected by permeability, shear rates, and sprout length. Increased permeability increases temporal WSS fluctuations; for example, at high permeability and a shear rate of 100 s⁻¹, variations near the sprout base can reach up to 30 dyne/cm². Shorter sprouts experience 3 to 4 times higher temporal WSS variations near the tip compared to longer sprouts. Moreover, the host vessel hematocrit actively influences temporal WSS variation along the sprout. At 20% hematocrit, WSS fluctuations range from 4 to 1 dyne/cm² across different shear rates. Additionally, time-averaged WSS and their gradients show significant dependency on shear rates for both high and regular permeabilities. Revealing such characteristics of sprouts provides a foundation for correlating hemodynamics with sprout growth.

Conclusions:
New findings from this work provide new characterizations of hemodynamics in blood vessel sprouts. The rich and unique WSS patterns (time-dependent and time-averaged), along with physiological permeability, provide a foundation for better understanding and predicting how new blood vessels grow, and provoke new discussions and studies.

Acknowledgements and/or References (Optional)::

References:
(1) Balogh et. al, JCP., 2017.

Acknowledgements:
NSF CBET 2309559, and Expanse at the San Diego Supercomputer Center and Anvil Supercomputer at Purdue University per NSF Accelerate Award BIO230073