Vasanthi Bathrinarayanan Pranav, Abadie Thomas, Perez Esteban Patricia, Vigolo D, Simmons M J H, Grover L M
School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
APL Bioeng. 2025 Aug 20;9(3):036113. doi: 10.1063/5.0275985. eCollection 2025 Sep.
Despite the effects of shear stress on endothelial biology having been extensively researched, the effects of hydrostatic vascular pressure at extremely low shear stresses have been largely ignored. In the current study, we employ a microfluidic organ-on-chip platform to elucidate the time and shear stress dependent effects of elevated hydrostatic pressure on endothelial junctional perturbations. We report that short term (1 h) exposure to elevated hydrostatic pressure at high shear stress (0.1 Pa) but not low shear stress (0.01 Pa) caused VE-cadherin to form finger like projections at the cell-cell junctions, and this effect was abrogated upon pharmacologically inhibiting cationic mechanosensitive channels using GsMTx4 peptide. Interestingly, prolonged exposure (24 h) to elevated hydrostatic pressure at low (0.01 Pa) but not high shear stress (0.1 Pa) caused disruption of VE-cadherin at cell-cell contacts and increased its cytoplasmic concentration. Furthermore, we report that this disruption of VE-cadherin was reversible upon pharmacologically inhibiting cationic mechanosensitive channels in a time-dependent manner; wherein after 12 h, we observed VE-cadherin reassemble at the cell-cell junctions. Overall, we demonstrate that cationic mechanosensitive channels play a crucial role in the mechanotransduction of elevated hydrostatic pressure by regulating the VE-cadherin dynamics at cell-cell junctions.
尽管剪切应力对内皮生物学的影响已得到广泛研究，但极低剪切应力下的流体静力血管压力的影响在很大程度上被忽视了。在本研究中，我们采用微流控芯片器官平台来阐明升高的流体静力压力对内皮连接扰动的时间和剪切应力依赖性影响。我们报告称，在高剪切应力（0.1 Pa）而非低剪切应力（0.01 Pa）下短期（1小时）暴露于升高的流体静力压力会导致VE-钙黏蛋白在细胞间连接处形成指状突起，并且使用GsMTx4肽药理学抑制阳离子机械敏感通道后这种效应会被消除。有趣的是，在低剪切应力（0.01 Pa）而非高剪切应力（0.1 Pa）下长时间（24小时）暴露于升高的流体静力压力会导致VE-钙黏蛋白在细胞间接触处被破坏并增加其细胞质浓度。此外，我们报告称，通过以时间依赖性方式药理学抑制阳离子机械敏感通道，VE-钙黏蛋白的这种破坏是可逆的；其中在12小时后，我们观察到VE-钙黏蛋白在细胞间连接处重新组装。总体而言，我们证明阳离子机械敏感通道通过调节细胞间连接处的VE-钙黏蛋白动态在升高的流体静力压力的机械转导中起关键作用。
