Estimation of 3D wall shear stress in new blood vessel sprouts using high-fidelity simulations

Angiogenesis, characterized by endothelial cell sprouting of new blood vessels off existing vessels, is a common denominator for normal physiological function and multiple diseases. Although it is generally accepted that local microvascular hemodynamics and wall shear stress (WSS) influence endothelial dynamics associated with capillary sprout growth, the current understanding is largely based on correlative observations and does not consider actual shear stress values affected by 3D details and red blood cell (RBC) flow present in vivo. To address this gap, we use 3D RBC-resolved simulations and digital reconstructions of in vivo blood vessel sprouts to quantify time-dependent 3D WSS characteristics experienced within sprouts. The findings reveal significant and physiologically relevant time-dependent WSS variations along the sprout length due to the naturally unsteady conditions in the host vessel caused by deformable RBC interactions. We identify how RBCs can enter a sprout and further exacerbate the WSS characteristics, behavior that can be influenced by both the sprout geometry and hemodynamic conditions. In absence of RBCs in a sprout, WSS magnitudes varied by as much as 4 dyne/cm2 at locations along the sprout length, whereas if an RBC entered the sprout, this variation magnitude increased to as much as 13 dyne/cm2. Our findings also demonstrate how shorter sprouts can experience greater WSS stimulation overall, notably at locations closer to the sprout tip. Further, reducing the host vessel diameter is shown to decrease the magnitude of time-dependent WSS fluctuations experienced within the sprout, whereas parametric studies on host vessel hematocrit and flow strength quantify how WSS magnitudes and fluctuations increase in direct proportion to both. Altogether, our work presents new estimations of 3D WSS characteristics experienced within in vivo sprouts influenced by deformable RBCs, complex sprout morphologies, and hemodynamic conditions. The results provide a foundation for understanding the shear stresses associated with capillary sprouts.