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bioRxiv · 10.1101/766816

Enhancement of endothelialization by topographical features is mediated by PTP1B-dependent endothelial adherens junctions remodeling

Gorji, A.·Toh, P. J. Y.·Toh, Y.-C.·Toyama, Y.·Kanchanawong, P.
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Abstract

RationaleFailure of small synthetic vascular grafts is largely due to late endothelialization and has been an ongoing challenge in the treatment of cardiovascular diseases.\n\nObjectivePrevious strategies developed to promote graft endothelialization include surface topographical modulation and biochemical modifications. However, these have been met with limited success. Importantly, although the integrity of Endothelial Cell (EC) monolayer is crucial for endothelialization, the crosstalk between surface topography and cell-cell connectivity is still not well understood. Here we explored a combined strategy that utilizes both topographical features and pharmacological perturbations.\n\nMethods and resultWe characterized EC behaviors in response to micron-scale grating topography in conjunction with pharmacological perturbations of endothelial adherens junctions (EAJ) regulators. We studied the EA.hy 926 cell-cell junctions and monolayer integrity using the junctional markers upon the inhibitory effect of EAJ regulator on both planar and grating topographies substrates.\n\nWe identified a protein tyrosine phosphatase, PTP1B, as a potent regulator of EAJ stability. Next, we studied the physiologically relevant behaviors of EC using primary human coronary arterial endothelial cells (HCAEC). Our results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration to promote endothelialization.\n\nOur results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration and proliferation.\n\nConclusionThe synergistic effect of PTP1B inhibition and grating topographies could be useful for the promotion of endothelialization by enhancing EC migration and proliferation.

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Gorji, A., Toh, P. J. Y., Toh, Y.-C., Toyama, Y., Kanchanawong, P.. 2019-09-16. Enhancement of endothelialization by topographical features is mediated by PTP1B-dependent endothelial adherens junctions remodeling. https://doi.org/10.1101/766816

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