Matrix Softening Induces Inflammatory Signals of Endothelial Cells

Abstract

Vascular diseases such as atherosclerosis involve the change of the rigidity in the blood vessel wall. There is evidence that the changes in the blood vessel rigidity may affect the various functions of the cells in the blood vessel, including endothelial cells (ECs) and the smooth muscle cells. On the other hand, blood vessel-on-a-chip has become an emerging research field for dis-ease modeling. However, the effect of material rigidity on blood vessel remodeling is not well understood. Hereby, an in vitro culture system with the culture substrates matching the rigidity of vessel wall mimicking the condition of healthy (normal) or lipid deposition (soft) were prepared. The stiffness of the substrates was confirmed by atomic force microscope. Although no significant difference was observed in EC morphology, the expression levels of the pro-inflammatory cytokines, including interleukin 6 (IL6), tumor necrosis factor α (TNF-α) and interleukin 1β (IL1β), were dramatically induced by soft substrate. Consistently, the inflammation-related JNK signaling was also activated. In addition, the expression level of microRNA-146a (miR-146a) was significantly decreased. Accordingly, mRNA expression level of TNF receptor associated factor 6 (TRAF6), the direct target of miR-146a, was significantly increased. In summary, these findings provide new insight into the matrix rigidity effect on ECs; while engineering the blood vessel model in vitro, matrix with proper rigidity can be carefully tailor to mimic ECs either in a quiescent or an inflammation state.