Previous in vitro studies have reported on the use of direct current electric fields (DC-EFs) to regulate vascular endothelial permeability, which is important for tissue regeneration and wound healing. However, these studies have primarily used static 2D culture models that lack the fluid mechanical forces associated with blood flow experienced by endothelial cells (ECs) in vivo. Hence, the effect of DC-EF on ECs under physiologically relevant fluid forces is yet to be systematically evaluated. Using a 3D microfluidic model of a bifurcating vessel, we report the role of DC-EF on regulating endothelial permeability when co-applied with physiologically relevant fluid forces that arise at the vessel bifurcation. The application of a 70 V m^-1 DC-EF simultaneously with 1 μL min^-1 low perfusion rate (generating 3.8 dyn cm^-2 stagnation pressure at the bifurcation point and 0.3 dyn cm^-2 laminar shear stress in the branched vessel) increased the endothelial permeability 7-fold compared to the static control condition (i.e., without flow and DC-EF). When the perfusion rate was increased to 10 μL min^-1 (generating 38 dyn cm^-2 stagnation pressure at the bifurcation point and 3 dyn cm^-2 laminar shear stress in the branched vessel) while maintaining the same electrical stimulation, a 4-fold increase in endothelial permeability compared to the static control was observed. The lower increase in endothelial permeability for the higher fluid forces but the same DC-EF suggests a competing role between fluid forces and the applied DC-EF. Moreover, the observed increase in endothelial permeability due to combined DC-EF and flow was transient and dependent on the Akt signalling pathway. Collectively, these findings provide significant new insights into how the endothelium serves as an electro-mechanical interface for regulating vessel permeability.

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