Utilization of an Artery‐on‐a‐Chip to Unravel Novel Regulators and Therapeutic Targets in Vascular Diseases

Abstract

In this study, organ‐on‐chip technology is used to develop an in vitro model of medium‐to‐large size arteries, the artery‐on‐a‐chip (AoC), with the objective to recapitulate the structure of the arterial wall and the relevant hemodynamic forces affecting luminal cells. AoCs exposed either to in vivo‐like shear stress values or kept in static conditions are assessed to generate a panel of novel genes modulated by shear stress. Considering the crucial role played by shear stress alterations in carotid arteries affected by atherosclerosis (CAD) and abdominal aortic aneurysms (AAA) disease development/progression, a patient cohort of hemodynamically relevant specimens was utilized, consisting of diseased and non‐diseased (internal control) vessel regions from the same patient. Genes activated by shear stress followed the same expression pattern in non‐diseased segments of human vessels. Single cell RNA sequencing enables us to discriminate the unique cell subpopulations between non‐diseased and diseased vessel portions, revealing an enrichment of flow activated genes in structural cells originating from non‐diseased specimens. Furthermore, the AoC served as a platform for drug‐testing. It reproduced the effects of a therapeutic agent (lenvatinib) previously used in preclinical AAA studies, therefore extending our understanding of its therapeutic effect through a multicellular structure.This article is protected by copyright. All rights reserved

Endothelial cannabinoid CB1 receptor deficiency reduces arterial inflammation and lipid uptake in response to atheroprone shear stress

“…We determined the expression of CB1 in human and mouse atherosclerotic vessels at the mRNA level due to the lack of specific antibodies to detect CB1 at the protein level. 34 In human plaque single cell RNA sequencing data from the Munich Vascular Biobank, 18 we detected CNR1 only in ECs, probably because the sensitivity of analysis was insufficient to detect CNR1 expressed by other plaque cell types. Remarkably, we found that endothelial CB1 expression is regulated by shear stress, revealing an increased receptor expression in atheroprone regions of mouse aortas and in HAoECs subjected to OSS.…”

“…While CB1 expression has been reported in human plaques, 17 the specific cell types contributing to CB1 signaling within the plaque have not been well characterized. Therefore, we screened single-cell RNA sequencing data from human carotid plaques 18 and found that the CB1-encoding gene CNR1 was detectable in plaque endothelial cells (Figure 1A-B). CNR1 expression was not detectable in other cell clusters of human atherosclerotic plaques identified by single cell RNA sequencing, although the expression has previously been demonstrated in a variety of immune cells 19 and more recently in murine plaque macrophages by in situ hybridization.…”