Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip

A three-dimensional microengineered human coronary artery-on-a-chip was developed for investigation of the mechanism by which low and oscillatory shear stress (OSS) induces pro-atherogenic changes. Single-cell RNA sequencing revealed that OSS induced distinct changes in endothelial cells ( ECs) including pro- inflammatory endothelial-to-mesenchymal transition (EndMT). OSS promoted pro-inflammatory EndMT through the Notch1/p38 MAPK-NF-kappa B signaling axis. Moreover, OSS-induced EC phenotypic changes resulted in proliferation and extracellular matrix (ECM) protein up-regulation in smooth muscle cells (SMCs) through the RANTES-mediated paracrine mechanism. IL-37 suppressed OSS-induced pro-inflammatory EndMT and thereby abrogated SMC proliferation and ECM protein remodeling. Overall, this study provides insights into endothelial heterogeneity under atheroprone shear stress and identifies the mechanistic role of a novel EC subtype in promoting adverse vascular remodeling. Further, this study demonstrates that anti-inflammatory approach is capable of mitigating vascular pathobiology evoked by atheroprone shear stress.

Automated summary

In this study, it was found that low and oscillatory shear stress can induce pro-inflammatory endothelial-to-mesenchymal transition, leading to smooth muscle cell proliferation and extracellular matrix protein up-regulation. IL-37 was shown to suppress this pro-inflammatory transformation, thereby preventing abnormal smooth muscle cell proliferation and ECM protein remodeling.