Abstract 14895: Shear Stress-induced Endothelial Inflammatory Response and EndMT Promote Adverse Remodeling in a Microengineered Coronary-artery-on-a-chip

Background: Atherosclerotic lesions preferentially occur at bifurcations and branching points where blood flow exerts low and bidirectional oscillatory shear stress (OSS) to the vascular walls. This study aims to determine the role of OSS in the induction of inflammatory activation and phenotypic transition in coronary artery endothelial cells and investigate the interaction between endothelial cells and smooth muscle cells in a coronary-artery-on-a-chip. Methods and Results: A three-dimensional microengineered human coronary-artery-on-a-chip was developed and incorporated with OSS to mimic the flow patterns within the microenvironment of coronary artery in atheroprone regions. Human coronary artery endothelial cells (HCAECs) were cultured on the upper surface of a collagen I-coated membrane, and human coronary artery smooth muscle cells (HCASMCs) were seeded on the opposite side of the membrane. Single-cell RNA sequencing analysis revealed that HCAECs were segregated into four subgroups after being exposed to OSS for 24 h, and inflammatory response and EndMT-related genes were enriched simultaneously in most HCAECs. OSS-induced inflammatory response and EndMT in HCAECs were confirmed by immunoblotting and immunofluorescence, and these changes were mediated by the Notch1/p38 MAPK-NF-κB signaling pathways. Moreover, HCAECs exposed to OSS induced extracellular matrix (ECM) protein remodeling and proliferation in HCASMCs through a paracrine mechanism. Multiplex ELISA analysis identified that RANTES exhibited the greatest increase after OSS in HCAEC culture and played a major role in modulation of ECM protein remodeling in HCASMCs. Further, IL-37 was able to prevent OSS-induced inflammatory response and EndMT in HCAECs and thereby abrogated ECM protein remodeling and proliferation in HCASMCs. Conclusion: OSS provokes inflammatory response and EndMT in HCAECs through activating the Notch1/p38 MAPK-NF-κB signaling pathways. The novel findings demonstrate that OSS-induced endothelial inflammatory response and associated EndMT promote vascular adverse remodeling and that anti-inflammatory cytokine IL-37 may have therapeutic potential for suppressing endothelial changes and resultant vascular adverse remodeling.