Elevated hydrostatic pressure modulates endothelial junctional mechanotransduction through VE-cadherin remodelling and altered association with YAP1, EPS8: an endothelium-on-chip study

Elevated hydrostatic pressure plays a crucial role in modulating endothelial junctional behavior, as demonstrated in a study employing a microfluidic platform. This pressure, when combined with low shear stress, induces significant changes in VE-cadherin junctions, leading to the formation of serrated, finger-like structures. These alterations are accompanied by increased nuclear localisation of YAP1 and reduced colocalisation with VE-cadherin, compared to shear stress alone conditions.

Additionally, there is an increase in cytoplasmic accumulation of EPS8, an actin adaptor protein, along with enhanced colocalisation with VE-cadherin. These changes are associated with heightened endothelial permeability and increased adhesion of THP-1 monocytes, suggesting the activation of mechanosensitive pathways. Inhibition of PI3K under elevated hydrostatic pressure results in a thinner VE-cadherin pattern and increased cytoplasmic colocalisation of EPS8, highlighting the critical role of PI3K signalling in regulating junction organisation.

Interestingly, Piezo-1 activation using Yoda1 yields context-dependent outcomes. While under shear stress alone, Yoda1 promotes YAP1 nuclear translocation, reduces YAP1-VE-cadherin colocalisation, and increases endothelial permeability without affecting THP-1 adhesion, under elevated hydrostatic pressure conditions, Yoda1 reduces both endothelial permeability and THP-1 adhesion, while simultaneously increasing YAP1-VE-cadherin colocalisation and decreasing YAP1 nuclear accumulation.

Overall, these findings reveal an underappreciated pathway involving elevated hydrostatic pressure, Piezo-1, and PI3K signalling that regulates endothelial barrier integrity and pro-adhesive endothelial activation through coordinated modulation of VE-cadherin, YAP1, and EPS8. This underscores the unique mechanobiological nature of elevated hydrostatic pressure, distinguishing it from shear stress alone, and sheds light on the underlying mechanisms of microvascular dysfunction.