Endothelial cells as mechanical transducers: enzymatic activity and network formation under cyclic strain.

A Shukla, A R Dunn, M A Moses, K J Van Vliet
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Abstract

Although it is established that endothelial cells can respond to external mechanical cues (e.g., alignment in the direction of fluid shear stress), the extent to which mechanical stress and strain applied via the endothelial cell substrate impact biomolecular and cellular processes is not well-understood. This issue is particularly important in the context of inflammation, vascular remodeling, and cancer progression, as each of these processes occurs concurrently with localized increases in strain and marked changes in molecules secreted by adjacent cells. Here, we systematically vary the level and duration of cyclic tensile strain applied to human dermal microvascular and bovine capillary endothelial cells via substrate deflection, and then correlate these cues with the secretion of extracellular matrix-degrading enzymes and a morphological transition from confluent monolayers to well-defined multicellular networks that resemble capillary tube-like structures. For a constant chemical environment, we find that super-physiological mechanical strain stimulates both endothelial cell secretion of latent matrix metalloprotease-2 and multicellular networks in a time- and strain-dependent manner. These results demonstrate coupling between the mechanical and biochemical states of microvascular endothelial cells, and indicate that elevated local stress may directly impact new capillary growth (angiogenesis) toward growing tumors and at capillary wall defect sites.

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内皮细胞作为机械换能器:循环应变下的酶活性和网络形成。
虽然内皮细胞可以响应外部机械信号(例如,流体剪切应力方向的对齐),但通过内皮细胞底物施加的机械应力和应变对生物分子和细胞过程的影响程度尚不清楚。这个问题在炎症、血管重塑和癌症进展的背景下尤为重要,因为这些过程中的每一个都伴随着局部应变的增加和邻近细胞分泌的分子的显著变化。在这里,我们系统地改变了通过底物挠曲作用于人皮肤微血管和牛毛细血管内皮细胞的循环拉伸应变的水平和持续时间,然后将这些线索与细胞外基质降解酶的分泌和从融合单层到类似毛细血管样结构的明确的多细胞网络的形态转变联系起来。对于恒定的化学环境,我们发现超生理机械应变以时间和应变依赖的方式刺激内皮细胞分泌潜伏基质金属蛋白酶-2和多细胞网络。这些结果证明了微血管内皮细胞的机械和生化状态之间的耦合,并表明局部应激升高可能直接影响肿瘤生长和毛细血管壁缺陷部位的新毛细血管生长(血管生成)。
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