Utilization of anArtery-on-a-chipto unravel novel regulators and therapeutic targets in vascular diseases

Abstract

AbstractIntroductionOrgans-on-chips represent novelin vitromodels that have the capacity to emulate aspects of human physiology and pathophysiology by incorporating features like tissue-multicellularity and exposure to organ-relevant physical environment. We developed anartery-on-a-chipwith the objective to recapitulate the structure of the arterial wall composed of intimal and medial layers and the relevant hemodynamic forces that affect luminal cells.ResultsBy comparingarteries-on-chipsexposed either toin vivo-like shear stress values or kept in static conditions, we identified a panel of novel genes modulated by shear stress. We next measured the expression pattern of shear stress-modulated genes in areas of the vascular tree affected by atherosclerotic plaques and aortic aneurysms, where disease development and progression are induced by alterations of shear stress. We obtained biopsies from patients affected by carotid artery disease (CAD), comprising the atherosclerotic plaque (diseased artery) and the adjacent region (non-diseased artery). From patients with abdominal aortic aneurysms (AAA), we obtained the aneurysmal portion (diseased aorta) and non-dilated adjacent segment (non-diseased aorta). Genes modulated by shear stress followed the same expression pattern in non-diseased segments of human vessels and were expressed by endothelial and smooth muscle cells as evidenced by immunofluorescence analysis and single cell RNA sequencing. Using mice and porcine models of vascular CAD and AAA, we confirmed that shear stress mediated targets are important in discriminating diseased and non-diseased vessel portionsin vivo. Furthermore, we showed that ourartery-on-a-chipcan serve as a platform for drug-testing. We were able to reproduce the effects of a therapeutic agent previously used in AAA animal models inartery-on-a-chipsystems and extend our understanding of its therapeutic effect through a multicellular structure.ConclusionsOur novelin vitromodel is capable of mimicking important physiological aspects of human arteries, such as the response to shear stress, and can further shed light on the mechanism of action of potential therapeutics before they enter the clinical stage.TeaserTheartery-on-a-chipis a novelin vitroplatform that enables the mimicry of human arteries and can be used to gain insights into the development and therapeutic targeting of vascular diseases.