Department of Mechanical and Aerospace Engineering, The Ohio State University, Scott Laboratory, 201 W. 19th Ave, Columbus, OH 43210, USA.
Lab Chip. 2018 Mar 27;18(7):1084-1093. doi: 10.1039/c8lc00130h.
Endothelial barrier function is known to be regulated by a number of molecular mechanisms; however, the role of biomechanical signals associated with blood flow is comparatively less explored. Biomimetic microfluidic models comprised of vessel analogues that are lined with endothelial cells (ECs) have been developed to help answer several fundamental questions in endothelial mechanobiology. However, previously described microfluidic models have been primarily restricted to single straight or two parallel vessel analogues, which do not model the bifurcating vessel networks typically present in physiology. Therefore, the effects of hemodynamic stresses that arise due to bifurcating vessel geometries on ECs are not well understood. Here, we introduce and characterize a microfluidic model that mimics both the flow conditions and the endothelial/extracellular matrix (ECM) architecture of bifurcating blood vessels to systematically monitor changes in endothelial permeability mediated by the local flow dynamics at specific locations along the bifurcating vessel structure. We show that bifurcated fluid flow (BFF) that arises only at the base of a vessel bifurcation and is characterized by stagnation pressure of ∼38 dyn cm-2 and approximately zero shear stress induces significant decrease in EC permeability compared to the static control condition in a nitric oxide (NO)-dependent manner. Similarly, intravascular laminar shear stress (LSS) (3 dyn cm-2) oriented tangential to ECs located downstream of the vessel bifurcation also causes a significant decrease in permeability compared to the static control condition via the NO pathway. In contrast, co-application of transvascular flow (TVF) (∼1 μm s-1) with BFF and LSS rescues vessel permeability to the level of the static control condition, which suggests that TVF has a competing role against the stabilization effects of BFF and LSS. These findings introduce BFF at the base of vessel bifurcations as an important regulator of vessel permeability and suggest a mechanism by which local flow dynamics control vascular function in vivo.
已知内皮屏障功能受多种分子机制调节；然而，与血流相关的生物力学信号的作用相对较少被探索。包含内皮细胞 (EC) 衬里的血管类似物的仿生微流控模型已被开发出来，以帮助回答内皮细胞机械生物学中的几个基本问题。然而，以前描述的微流控模型主要限于单个直的或两个平行的血管类似物，它们不能模拟生理上常见的分叉血管网络。因此，由于分叉血管几何形状引起的血液动力学应力对 EC 的影响还不太清楚。在这里，我们引入并描述了一种微流控模型，该模型模拟了分叉血管的流动条件和内皮/细胞外基质 (ECM) 结构，以系统地监测沿分叉血管结构特定位置的局部流动动力学介导的内皮通透性变化。我们表明，仅在血管分叉底部产生的分叉流体流动 (BFF) 具有约 38 dyn cm-2 的停滞压力和几乎为零的剪切应力，与静态对照条件相比，以一氧化氮 (NO) 依赖性方式显著降低 EC 的通透性。类似地，位于血管分叉下游的 EC 处的血管内层流剪切应力 (LSS) (3 dyn cm-2) 沿切线方向也会导致通透性与静态对照条件相比显著降低，这是通过 NO 途径实现的。相比之下，跨血管流动 (TVF) (∼1 μm s-1) 与 BFF 和 LSS 的共同应用可将血管通透性恢复到静态对照条件的水平，这表明 TVF 具有与 BFF 和 LSS 的稳定作用竞争的作用。这些发现将分叉处的 BFF 引入血管通透性的重要调节因子，并提出了一种局部流动动力学控制体内血管功能的机制。
