Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase.

HSIAO, Sarah T, SPENCER, Timothy, BOLDOCK, Luke, PROSSEDA, Svenja Dannewitz, XANTHIS, Ioannis, TOVAR-LOPEZ, Francesco J, VAN BUESEKAMP, Heleen, KHAMIS, Ramzi Y, FOIN, Nicolas, BOWDEN, Neil, HUSSAIN, Adil, ROTHMAN, Alex, RIDGER, Victoria, HALLIDAY, Ian, PERRAULT, Cecile, GUNN, Julian and EVANS, Paul C (2016). Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase. Cardiovascular Research. (In Press)

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Link to published version:: 10.1093/cvr/cvw210

Abstract

Aims: Stent deployment causes endothelial cell (EC) denudation, which promotes in-stent restenosis and thrombosis. Thus endothelial regrowth in stented arteries is an important therapeutic goal. Stent struts modify local hemodynamics, however the effects of flow pertubation on EC injury and repair are incompletely understood. By studying the effects of stent struts on flow and EC migration we identified an intervention that promotes endothelial repair in stented arteries. Methods and Results: In vitro and in vivo models were developed to monitor endothelialization under flow and the influence of stent struts. A 2D parallel-plate flow chamber with 100 μm ridges arranged perpendicular to the flow was used. Live cell imaging coupled to computational fluid dynamic simulations revealed that EC migrate in the direction of flow upstream from the ridges but subsequently accumulate downstream from ridges at sites of bidirectional flow. The mechanism of EC trapping by bidirectional flow involved reduced migratory polarity associated with altered actin dynamics. Inhibition of Rho-associated protein kinase (ROCK) enhanced endothelialization of ridged surfaces by promoting migratory polarity under bidirectional flow (p<0.01). To more closely mimic the in vivo situation we cultured EC on the inner surface of polydimethylsiloxane tubing containing Coroflex Blue stents (65 μm struts) and monitored migration. ROCK inhibition significantly enhanced EC accumulation downstream from struts under flow (p<0.05). We investigated the effects of ROCK inhibition on re-endothelialization in vivo using a porcine model of EC denudation and stent placement. En face staining and confocal microscopy revealed that inhibition of ROCK using fasudil (30 mg/day via osmotic minipump) significantly increased re-endothelialization of stented carotid arteries (p<0.05). Conclusions: Stent struts delay endothelial repair by generating localised bidirectional flow which traps migrating EC. ROCK inhibitors accelerate endothelial repair of stented arteries by enhancing EC polarity and migration through regions of bidirectional flow.

Item Type: Article
Research Institute, Centre or Group: Materials and Engineering Research Institute > Polymers Nanocomposites and Modelling Research Centre > Materials and Fluid Flow Modelling Group
Identification Number: 10.1093/cvr/cvw210
SWORD Depositor: Ann Betterton
Depositing User: Ann Betterton
Date Deposited: 19 Oct 2016 10:31
Last Modified: 14 Jun 2017 17:06
URI: http://shura.shu.ac.uk/id/eprint/13815

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