Controlled disturbed flows on the endothelium result in increased inflammation, nuclear lamin disruption and heterochromatin condensation

Abstract

AbstractEarly atherosclerotic lesions often develop in arterial bifurcations and curvatures that experience complex disturbed flows. Lab-on-chip devices primarily adopt laminar unidirectional and oscillatory flows to characterize endothelial mechanobiology and test therapeutics. Such flows do not reproduce the time-varying, bidirectional, and complicated shear patterns on arterial walls. We fabricated an endothelium-on-chip device and developed a semi-analytical model to produce any prescribed wall shear pattern characterized by a shear rosette. We quantified responses of Human Aortic Endothelial Cell (HAEC) monolayers subjected to unidirectional laminar (Uni-L) and oscillatory (Uni-O) flows in straight microfluidic channels, and a circular shear rosette (Bi-O), defined by bidirectional oscillatory flows, in the new device. Immunofluorescence results show well-defined stress fibers and VE-cadherin under laminar flows. Cells were more cuboidal with significantly larger nuclear areas in the device as compared to other groups. Lamin A/C disruption and heterochromatin reorganization were evident in nuclei of cells in the Bi-O group but were absent in the Uni-L and No-flow control groups. Cells showed significantly elevated actin, VE-cadherin, inflammatory NF-kB, and lamin expressions in the device compared to other groups. A device to create controlled disturbed flows offers a platform to assess mechanobiology, has significant potential in personalized medicine, and reduces reliance on animal trials.