To form blood vessels, endothelial cells rearrange their cytoskeleton, generate traction stresses, migrate, and proliferate, all of which require energy. Despite these energetic costs, stiffening of the extracellular matrix promotes tumor angiogenesis and increases cell contractility. However, the interplay between extracellular matrix, cell contractility, and cellular energetics remains mechanistically unclear. Here, we utilized polyacrylamide substrates with various stiffnesses, a real-time biosensor of ATP, and traction force microscopy to show that endothelial cells exhibit increasing traction forces and energy usage trend as substrate stiffness increases. Inhibition of cytoskeleton reorganization via ROCK inhibition resulted in decreased cellular energy efficiency, and an opposite trend was found when cells were treated with manganese to promote integrin affinity. Altogether, our data reveal a link between matrix stiffness, cell contractility, and cell energetics, suggesting that endothelial cells on stiffer substrates can better convert intracellular energy into cellular traction forces. Given the critical role of cellular metabolism in cell function, our study also suggests that not only energy production but also the efficiency of its use plays a vital role in regulating cell behaviors and may help explain how increased matrix stiffness promotes angiogenesis.

中文翻译：

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基质硬度提高内皮细胞的能量效率


为了形成血管，内皮细胞重新排列其细胞骨架、产生牵引应力、迁移和增殖，所有这些都需要能量。尽管存在这些能量消耗，细胞外基质的硬化仍促进肿瘤血管生成并增加细胞收缩性。然而，细胞外基质、细胞收缩性和细胞能量学之间的相互作用在机制上仍不清楚。在这里，我们利用具有不同硬度的聚丙烯酰胺基底、ATP 的实时生物传感器和牵引力显微镜来表明，随着基底硬度的增加，内皮细胞表现出增加的牵引力和能量使用趋势。通过 ROCK 抑制来抑制细胞骨架重组会导致细胞能量效率降低，而当用锰处理细胞以促进整合素亲和力时，发现了相反的趋势。总而言之，我们的数据揭示了基质刚度、细胞收缩性和细胞能量之间的联系，表明较硬基质上的内皮细胞可以更好地将细胞内能量转化为细胞牵引力。鉴于细胞代谢在细胞功能中的关键作用，我们的研究还表明，不仅能量产生而且其使用效率在调节细胞行为中起着至关重要的作用，并且可能有助于解释增加的基质硬度如何促进血管生成。