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Endothelial cell forward migration in a disturbed wall shear stress environment is promoted by ROCK inhibition

About the abstract of Sarah Hsiao, Associate Faculty Member, University of Sheffield Medical School, UK

Sarah Hsiao received the Young Investigator Awarded at the FCVB meeting 2014 as reward for her abstract about “Endothelial cell forward migration in a disturbed wall shear stress environment is promoted by ROCK inhibition”. 

Basic Sciences, Pharmacology, Genomics and Cardiovascular Pathology

Stent deployment is successfully used to treat patients with stenosed arteries across the world; however, the procedure may lead to severe damage of the endothelium. In a small population of patients this can trigger life-threatening events of thrombosis or in-stent restenosis. The work by S. Hsiao and co-workers hypothesized that the adverse effect of a localized disturbance in wall shear stress caused by stent struts contributes to the delayed re-endothelialisation, and that inhibition of culprit signaling pathways has the therapeutic potential to encourage endothelial repair post-stenting. To this end, using an in vitro model of stented vessels, the authors demonstrated that the presence of stent struts altered the wall shear stress pattern to generate a flow re-circulation zone downstream of the struts.

In comparison to the linear and efficient migratory pattern in the direction of flow under undisturbed flow, endothelial cells within the re-circulation zone displayed a loss of directionality and reduced average velocity. Based on the observation that disturbed flow impeded forward cell movement, the authors proposed that uncoupling of flow from endothelial cell migration might promote re-endothelialisation within the re-circulation zone. The small Rho GTPase family is a major regulator of cell migration; in particular, the RhoA-ROCK signaling axis has been suggested to determine cell directionality under flow through a mechanism that is poorly understood.

As hypothesized, the presence of ROCK inhibitor severed the linkage between wall shear stress and cell directionality, where the endothelial cells within the re-circulation zone exhibited efficient forward migration despite the presence of flow disturbance. The authors conclude that disturbed wall shear stress incurred by stent strut-like geometry disrupted endothelial cell forward migration in vitro and inhibition of the RhoA/ROCK signaling cascade rescued the lost of directionality.

The investigators are currently testing their findings in a preclinical in vivo model. They are assessing the effect of ROCK inhibition in promoting efficient post-stenting re-endothelialisation in porcine coronary arteries. The results generated from these studies may help to design new drug-eluting stents, where the incorporation of a ROCK inhibitor may enhance the rate of re-endothelialisation and reduce the rate of complications that occur in the setting of percutaneous coronary interventions.