Beyond Contractility: Fibroblast-Like VSMCs in Atherosclerotic Crosstalk

Introduction

Single-cell sequencing has advanced our understanding of cellular diversity in atherosclerosis. Yet how cells are spatially distributed within the plaque microenvironment, how they communicate with one another, and how these interactions affect plaque stability and clinical outcomes remains unknown.

Uncovering Intercellular Communication and Plaque Stability

In a recent study¹, Isabel Goncalves and colleagues delineated the spatial landscape of cellular communication in advanced human atherosclerotic plaques. By integrating spatial transcriptomics, single-cell RNA sequencing, bulk RNA sequencing, immunohistochemistry, in vitro experiments, mouse models, genome-wide association studies and clinical data, the authors constructed for the first time a comprehensive spatial map of not only plaque cell distribution but most interestingly of their intercellular communication, providing an important resource in the human atherosclerosis field. Additionally, they identified a cap-enriched fibroblast-like vascular smooth muscle cell (VSMC) population as key intercellular “communicators”, associated with collagen formation. These fibroblast-like VSMCs were more abundant and exhibited enhanced intercellular communication in asymptomatic plaques, and their abundance inversely correlated with histological plaque vulnerability and the risk of future cardiovascular events. Furthermore, in silico drug screening, followed by in vitro validation, suggested that targeting this cell phenotype may offer promising therapeutic opportunities.

Towards Novel Therapeutic Strategies for Plaque Stabilisation

Together, this work provides the first comprehensive spatial map of intercellular communication across distinct “geographical” regions of advanced human atherosclerotic plaques from symptomatics and asymptomatics. By identifying spatially localized, highly interactive cell phenotypes and how they communicate in situ this study opens for the discovery of novel therapeutic targets for stabilizing plaques and modulating human atherosclerosis.