Encompassing view of spatial and single-cell RNA-seq renews the role of the microvasculature in human atherosclerosis

Atherosclerosis is a pervasive contributor to cardiovascular diseases including ischemic heart disease and stroke. Despite the advance and success of effective lipid lowering-therapies and hypertensive agents, the residual risk of an atherosclerotic event remains high and improving disease understanding and development of novel therapeutic strategies has proven to be challenging. This is largely due to the complexity of atherosclerosis with a spatial interplay of multiple cell types within the vascular wall. Here, we generated an integrative high-resolution map of human atherosclerotic plaques by combining single-cell RNA-seq from multiple studies and novel spatial transcriptomics data from 12 human specimens to gain insights into disease mechanisms. Comparative analyses revealed cell-type and atherosclerosis-specific expression changes and associated alterations in cell-cell communication. We highlight the possible recruitment of lymphocytes via different endothelial cells of the vasa vasorum, the migration of vascular smooth muscle cells towards the lumen to become fibromyocytes, and cell-cell communication in the plaque, indicating an intricate cellular interplay within the adventitia and the subendothelial space in human atherosclerosis. ### Competing Interest Statement MN, HH, CP, MB, SB and VD are employed by Novo Nordisk A/S, which generated the spatial transcriptomics data. They hold minor stock portions as part of an employee-offering program. SH is a co-founder and shareholder of Sequantrix GmbH and has research funding from Novo Nordisk and Askbio. RK is a founder, shareholder and board member of Sequantrix GmbH, a member of the scientific advisory board of Hybridize Therapeutics, has received honoraria for advisory boards and talks from Bayer, Chugai, Pfizer, Roche, Genentech, Lilly and GSK and has research funding from Travere Therapeutics, Galapagos, Novo Nordisk and AskBio. All other authors indicated that no competing interests exist.