Oxygen gradients dictate angiogenesis but not barriergenesis in a 3D brain microvascular model
Oxygen gradients dictate angiogenesis but not barriergenesis in a 3D brain microvascular model
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DOI：
10.1002/jcp.30840
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发表时间：
2022-07-28
影响因子：
5.6
通讯作者：
Galie，Peter A.
中科院分区：
文献类型：
--
作者：
Tran，Kiet A.;Baldwin-Leclair，Abigail;Galie，Peter A.
已知多种生物物理特性可调节血管生成萌芽，体外系统可以在受控环境中解析这些因素的个体影响。在这里，三维脑微血管模型探讨了细胞外基质组成、流体剪切应力和曲率半径等变量如何影响脑内皮细胞的血管生成。几天内跟踪内皮迁移表明，施加流体剪切应力和扩大血管曲率半径都会减弱出芽。由耗氧量测定提供的计算模型表明，发芽与氧浓度降低相关：流体剪切应力和血管几何形状都会改变由环境条件和细胞呼吸决定的局部氧水平。此外，增加细胞密度并因此降低局部氧气水平会显着增加发芽率。进一步的分析表明，氧气浓度的大小并不像其空间浓度梯度那么重要：与向容器施加外部氧气梯度相比，降低环境氧气浓度会导致发芽明显减少。相反，屏障生成是由独立于局部氧浓度的剪切应力决定的，这表明不同的机制介导血管生成和屏障形成，并且血管生成萌芽可以在不损害屏障的情况下发生。总体而言，这些结果提高了我们对特定生物物理变量如何调节脑血管系统的功能和激活的理解，并将空间氧梯度确定为大脑血管生成的驱动因素。
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.