Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, USA.
Integr Biol (Camb). 2012 Aug;4(8):863-74. doi: 10.1039/c2ib00184e. Epub 2012 Jun 7.
A bias towards angiogenesis from the venous circulation has long been known, but its cause remains unclear. Here we explore the possibility that high interstitial pressure in tumors and the resultant net filtration pressure gradient that would induce flow from the interstitium into the venous circulation or lymphatics could also be an important mechanical regulator of angiogenesis. The objective of this study was to test the hypothesis that basal-to-apical (B-A) transendothelial flow promotes angiogenesis and to investigate potential mechanisms. Macro- and microvascular endothelial monolayers were cultured on type I collagen gels in a microfluidic cell culture device and subjected to apical-to-basal (A-B) and B-A transendothelial flows. Samples were perfusion fixed and analyzed for morphological responses, localization and degree of phosphorylation of certain signaling proteins. Application of B-A, but not A-B flow, to cultured endothelial monolayers was found to promote capillary morphogenesis and resulted in distinct localization patterns of VE-cadherin and increased FAK phosphorylation. These results suggest that B-A flow triggers the transition of vascular endothelial cells from a quiescent to invasive phenotype and that the flow-mediated response involves signaling at cell-cell and cell-matrix interfaces. These results support the hypothesis that transendothelial pressure gradients resulting in B-A flow promotes sprouting angiogenesis and are consistent with early observations that tumor angiogenesis occurs from the venous side of the circulation.
长期以来，人们一直知道静脉循环存在向血管生成的偏向，但其原因仍不清楚。在这里，我们探讨了这样一种可能性，即肿瘤中的间质压力高，以及由此产生的净过滤压力梯度会导致间质中的血流进入静脉循环或淋巴管，这也可能是血管生成的一个重要机械调节因子。本研究的目的是检验这样一个假设，即基底到顶端（B-A）的跨内皮流促进血管生成，并探讨潜在的机制。宏观和微血管内皮单层在微流体细胞培养装置中的 I 型胶原凝胶上培养，并施加顶端到基底（A-B）和 B-A 的跨内皮流。对样品进行灌注固定，并分析形态反应、某些信号蛋白的定位和磷酸化程度。发现 B-A 流（而不是 A-B 流）作用于培养的内皮单层可促进毛细血管形态发生，并导致 VE-钙粘蛋白的定位模式明显不同，并增加 FAK 的磷酸化。这些结果表明，B-A 流引发血管内皮细胞从静止到侵袭表型的转变，而这种流介导的反应涉及细胞-细胞和细胞-基质界面的信号转导。这些结果支持这样一种假设，即导致 B-A 流的跨内皮压力梯度促进了芽生血管生成，并且与早期观察到的肿瘤血管生成发生在循环的静脉侧一致。
