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Direct current electric field regulates endothelial permeability under physiologically relevant fluid forces in a microfluidic vessel bifurcation model.

ABSTRACT: 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.

SUBMITTER: Mohana Sundaram P

PROVIDER: S-EPMC7855772 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Endothelial barrier function is known to be regulated by a number of molecular mechanisms; however, the role of biomechanical signals associated with blood flow is comparatively less explored. Biomimetic microfluidic models comprised of vessel analogues that are lined with endothelial cells (ECs) have been developed to help answer several fundamental questions in endothelial mechanobiology. However, previously described microfluidic models have been primarily restricted to single straight or two parallel vessel analogues, which do not model the bifurcating vessel networks typically present in physiology. Therefore, the effects of hemodynamic stresses that arise due to bifurcating vessel geometries on ECs are not well understood. Here, we introduce and characterize a microfluidic model that mimics both the flow conditions and the endothelial/extracellular matrix (ECM) architecture of bifurcating blood vessels to systematically monitor changes in endothelial permeability mediated by the local flow dynamics at specific locations along the bifurcating vessel structure. We show that bifurcated fluid flow (BFF) that arises only at the base of a vessel bifurcation and is characterized by stagnation pressure of ?38 dyn cm-2 and approximately zero shear stress induces significant decrease in EC permeability compared to the static control condition in a nitric oxide (NO)-dependent manner. Similarly, intravascular laminar shear stress (LSS) (3 dyn cm-2) oriented tangential to ECs located downstream of the vessel bifurcation also causes a significant decrease in permeability compared to the static control condition via the NO pathway. In contrast, co-application of transvascular flow (TVF) (?1 ?m s-1) with BFF and LSS rescues vessel permeability to the level of the static control condition, which suggests that TVF has a competing role against the stabilization effects of BFF and LSS. These findings introduce BFF at the base of vessel bifurcations as an important regulator of vessel permeability and suggest a mechanism by which local flow dynamics control vascular function in vivo.

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Direct current electric field regulates endothelial permeability under physiologically relevant fluid forces in a microfluidic vessel bifurcation model.

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