Mechanical Engineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea.
Interdisciplinary Program for Bioengineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea.
Lab Chip. 2016 Oct 18;16(21):4189-4199. doi: 10.1039/c6lc00910g.
A crucial yet ill-defined phenomenon involved in the remodeling of vascular networks, including angiogenic sprouting, is flow-mediated endothelial dynamics and phenotype changes. Despite interstitial flow (IF) being ubiquitously present in living tissues surrounding blood capillaries, it is rarely investigated and poorly understood how endothelial cells respond to this flow during morphogenesis. Here we develop a microfluidic 3D in vitro model to investigate the role of IF during vasculogenic formation and angiogenic remodeling of microvascular networks. In the presented model, human blood endothelial cells co-cultured with stromal fibroblasts spontaneously organize into an interconnected microvascular network and then further expand to adjacent avascular regions in a manner of neovessel sprouting. We found that in the presence of IF, vasculogenic organization of the microvascular network was significantly facilitated regardless of the flow direction, whereas angiogenic sprouting was promoted only when the directions of flow and sprouting were opposite while angiogenic activity was suppressed into the direction of flow. We also observed that the vasculatures switch between active angiogenic remodeling and quiescent/non-sprouting state in the contexts provided by IF. This regulatory effect can be utilized to examine the role of anti-angiogenic compounds, clearly distinguishing the differential influences of the compounds depending on their mechanisms of action. Collectively, these results suggest that IF may serve as a critical regulator in tissue vascularization and pathological angiogenesis.
血管网络重塑过程中涉及到一个关键但尚未明确的现象，包括血管生成发芽，这就是血流介导的内皮动力学和表型变化。尽管间质流（IF）普遍存在于围绕毛细血管的活体组织中，但内皮细胞在形态发生过程中如何响应这种流动的问题很少被研究，也了解甚少。在这里，我们开发了一种微流控 3D 体外模型，以研究 IF 在血管生成形成和微血管网络血管生成重塑过程中的作用。在提出的模型中，与人血管内皮细胞共培养的基质成纤维细胞自发组织成相互连接的微血管网络，然后以新血管发芽的方式进一步扩展到相邻的无血管区域。我们发现，无论血流方向如何，IF 的存在都显著促进了微血管网络的血管生成组织，而血管生成发芽仅在血流方向与发芽方向相反时才会被促进，而在血流方向上则会抑制血管生成活性。我们还观察到，在 IF 提供的背景下，脉管系统在活跃的血管生成重塑和静止/非发芽状态之间切换。这种调节作用可用于研究抗血管生成化合物的作用，根据其作用机制清楚地区分化合物的不同影响。总的来说，这些结果表明，IF 可能是组织血管生成和病理性血管生成的关键调节因子。
