Modeling early stage atherosclerosis in a primary human vascular microphysiological system

Muath Bishawi,Varun Prasad,Ge Zhang,Qiao Zhang,Jason J. Breithaupt,Xu Zhang,Ellen Salmon,George A. Truskey

doi:10.1038/s41467-020-19197-8

Abstract

Novel atherosclerosis models are needed to guide clinical therapy. Here, we report an in vitro model of early atherosclerosis by fabricating and perfusing multi-layer arteriole-scale human tissue-engineered blood vessels (TEBVs) by plastic compression. TEBVs maintain mechanical strength, vasoactivity, and nitric oxide (NO) production for at least 4 weeks. Perfusion of TEBVs at a physiological shear stress with enzyme-modified low-density-lipoprotein (eLDL) with or without TNFα promotes monocyte accumulation, reduces vasoactivity, alters NO production, which leads to endothelial cell activation, monocyte accumulation, foam cell formation and expression of pro-inflammatory cytokines. Removing eLDL leads to recovery of vasoactivity, but not loss of foam cells or recovery of permeability, while pretreatment with lovastatin or the P2Y11 inhibitor NF157 reduces monocyte accumulation and blocks foam cell formation. Perfusion with blood leads to increased monocyte adhesion. This atherosclerosis model can identify the role of drugs on specific vascular functions that cannot be assessed in vivo.

Highlights

Novel atherosclerosis models are needed to guide clinical therapy
Inflammation plays an important role in the development and clinical presentation of atherosclerosis[7,8], and significantly higher rates of atherosclerosis occur in individuals with autoimmune disease, such as rheumatoid arthritis (RA)[9,10,11]
To enhance the overall concentration of collagen and improve the mechanical properties of tissue-engineered blood vessels (TEBVs), application of plastic compression removed over 90% of the water (Fig. S2)

Summary

Introduction

Novel atherosclerosis models are needed to guide clinical therapy. Here, we report an in vitro model of early atherosclerosis by fabricating and perfusing multi-layer arteriole-scale human tissue-engineered blood vessels (TEBVs) by plastic compression. Perfusion of TEBVs at a physiological shear stress with enzyme-modified low-density-lipoprotein (eLDL) with or without TNFα promotes monocyte accumulation, reduces vasoactivity, alters NO production, which leads to endothelial cell activation, monocyte accumulation, foam cell formation and expression of pro-inflammatory cytokines. Perfusion with blood leads to increased monocyte adhesion. This atherosclerosis model can identify the role of drugs on specific vascular functions that cannot be assessed in vivo. Monocytes enter and differentiate into macrophages, joined by proliferation of resident macrophages[4,5] This is a critical step in the process, as this pool of macrophages accumulate cholesterol from modified LDL in an unregulated fashion by scavenger receptors, forming foam cells[2,6].

Methods

Results

Conclusion