Pulsatile low shear stress increases susceptibility to endothelial inflammation via upregulation of IFT and activation of YAP.

Abstract

This study describes the development of a microfluidic chip model of the coronary artery endothelium and its use to examine the mechanism through which pulsatile shear stress regulates inflammation. The chip successfully recapitulates increased susceptibility to cytokine mediated arterial inflammation as observed in vivo in areas of low shear stress (LSS). Previous in vivo data show that low shear stress in the porcine aorta modulates 36 cilia-associated genes of which five are also Yes-associated protein (YAP) target genes. We demonstrate that pulsatile low shear stress (LSS) compared to high shear stress (HSS) preferentially drives YAP nuclear translocation and expression of the YAP target gene, Myosin Heavy Chain 10 (MYH10), which is also one of the cilia genes regulated by shear stress in vivo. LSS also increases expression of the cilia intraflagellar transport protein gene, IFT88, resulting in an increase in the primary cilia length and prevalence. Using a combination of siRNA and pharmaceutical regulators, we show that these changes in YAP, IFT88, and MYH10 drive the increased susceptibility to pro-inflammatory cytokines caused by LSS. Hence, we demonstrate that pulsatile LSS primes endothelial cells, increasing susceptibility to inflammation, and that this occurs through a novel pathway involving modulation of YAP and primary cilia/IFT. Such changes may also influence other cilia and YAP dependent responses. In conclusion, our microfabricated endothelial chip model reveals involvement of mechanosensitive IFT and YAP in arterial inflammation, which may provide novel therapeutic targets for the management of vascular disease such as atherosclerosis.