Yates Alexis K, Murray Heather, Kjar Andrew, Chavarria Daniel, Masters Haley, Kim Hyosung, Ligocki Alexander P, Jefferson Angela L, Lippmann Ethan S
Interdisciplinary Materials Science Program, Vanderbilt University, Nashville, TN, USA.
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Fluids Barriers CNS. 2025 Jul 15;22(1):73. doi: 10.1186/s12987-025-00683-4.
Brain endothelial cells experience mechanical forces in the form of blood flow-mediated shear stress and underlying matrix stiffness, but intersectional contributions of these factors towards blood-brain barrier (BBB) impairment and neurovascular dysfunction have not been extensively studied. Here, we developed in vitro models to examine the sensitivity of primary human brain microvascular endothelial cells (BMECs) to substrate stiffness, with or without exposure to fluid shear stress. Using a combination of molecular profiling techniques, we show that BMECs exhibit an inflammatory signature at both the mRNA and protein level when cultured on gelatin substrates of intermediate stiffness (~ 30 kPa) versus soft substrates (~ 6 kPa). Exposure to modest fluid shear stress (1.7 dyne/cm) partially attenuated this signature, including reductions in levels of soluble chemoattractants and surface ICAM-1. Overall, our results indicate that increased substrate stiffness promotes an inflammatory phenotype in BMECs that is dampened in the presence of fluid shear stress.
脑内皮细胞会受到血流介导的剪切应力和潜在基质硬度形式的机械力影响，但这些因素对血脑屏障（BBB）损伤和神经血管功能障碍的交叉作用尚未得到广泛研究。在此，我们建立了体外模型，以研究原代人脑微血管内皮细胞（BMECs）对基质硬度的敏感性，无论是否暴露于流体剪切应力。通过结合分子分析技术，我们发现，与软基质（约6 kPa）相比，当在中等硬度（约30 kPa）的明胶基质上培养时，BMECs在mRNA和蛋白质水平上均表现出炎症特征。暴露于适度的流体剪切应力（1.7达因/平方厘米）会部分减弱这种特征，包括可溶性化学引诱剂水平和表面ICAM-1水平的降低。总体而言，我们的结果表明，增加的基质硬度会促进BMECs中的炎症表型，而在存在流体剪切应力的情况下这种表型会受到抑制。
