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April 1st, 2025
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School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
bioengineering
biorxiv

Elevated hydrostatic pressure acts via piezo-1 to destabilise VE-cadherin junctions: an endothelium-on-chip study

Bathrinarayanan, P. V.Open in Google Scholar•Abadie, T.Open in Google Scholar•Esteban, P. P.Open in Google Scholar•Vigolo, D.Open in Google Scholar•Simmons, M. J. H.Open in Google Scholar•Grover, L. M.Open in Google Scholar

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 (1h) exposure to elevated hydrostatic pressure at high shear stress (1 dyne/cm2) but not low shear stress (0.1 dyne/cm2) caused VE-cadherin to form serrated, finger like projections at the cell-cell junctions and this effect was abrogated upon pharmacologically inhibiting piezo-1 mechanosensory protein. Interestingly, prolonged exposure (24h) to elevated hydrostatic pressure at low (0.1 dyne/cm2) but not high shear stress (1 dyne/cm2) caused VE-cadherin internalisation, thereby increasing the cytoplasmic concentration. Further, we report that this internalisation of VE-cadherin was reversible upon pharmacologically inhibiting piezo-1 in a time-dependent manner wherein after 12h, we observed stable VE-cadherin junctions re-appear at the cell-cell junctions. Overall, we demonstrate that piezo-1 plays a crucial role in the mechanotransduction of elevated hydrostatic pressure by regulating the VE-cadherin dynamics at cell-cell junctions. Targeting piezo-1 may provide a novel therapeutic/diagnostic marker, especially in conditions that involve microvascular dysfunction due to elevated vascular pressures.

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