Oxygen gradients dictate angiogenesis but not barriergenesis in a 3D brain microvascular model

Abstract

A variety of biophysical properties are known to regulate angiogenic sprouting, and in vitro systems can parse the individual effects of these factors in a controlled setting. Here, a three‐dimensional brain microvascular model interrogates how variables including extracellular matrix composition, fluid shear stress, and radius of curvature affect angiogenic sprouting of cerebral endothelial cells. Tracking endothelial migration over several days reveals that application of fluid shear stress and enlarged vessel radius of curvature both attenuate sprouting. Computational modeling informed by oxygen consumption assays suggests that sprouting correlates to reduced oxygen concentration: both fluid shear stress and vessel geometry alter the local oxygen levels dictated by both ambient conditions and cellular respiration. Moreover, increasing cell density and consequently lowering the local oxygen levels yields significantly more sprouting. Further analysis reveals that the magnitude of oxygen concentration is not as important as its spatial concentration gradient: decreasing ambient oxygen concentration causes significantly less sprouting than applying an external oxygen gradient to the vessels. In contrast, barriergenesis is dictated by shear stress independent of local oxygen concentrations, suggesting that different mechanisms mediate angiogenesis and barrier formation and that angiogenic sprouting can occur without compromising the barrier. Overall, these results improve our understanding of how specific biophysical variables regulate the function and activation of cerebral vasculature, and identify spatial oxygen gradients as the driving factor of angiogenesis in the brain.

Technology for the formation of engineered microvascular network models and their biomedical applications

“…Tran et al found no significant difference in cerebral microvascular germination between normoxia and 1% oxygen. However, an external oxygen gradient significantly increased neovascularization sprouting, leading to angiogenesis [ 164 ].…”

Representing unsegmented vessels using available vascular data for bioheat transfer simulation

“…One option to simulate the pre-capillary vessels from this point would be the mathematical modeling of blood vessels or an algorithm to simulate vascularization. Vascularization and angiogenesis are highly complex phenomena that include chemical, physical, and biological processes [14][15][16][17][18] . Vascular Endothelial Growth Factor (VEGF) signaling released by the tissue cells directs the tip cell to guide vascularization.…”