Elevated hydrostatic pressure destabilizes VE-cadherin junctions in a time and shear stress dependent manner: An endothelium-on-chip study.

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.