Under the magnifying glass: plaque-site specific gene signatures identify rupture prone areas

The atherosclerotic plaque is characterized by a complex composition that can be visualized by histology. Plaque components, including necrotic cores, fibrous caps, intraplaque haemorrhage as well as inflammatory infiltrates have a unique spatial distribution in the plaque which is associated with atherosclerotic plaque vulnerability.

The laboratory of Prof. Isabel Goncalves at Lund University (Sweden) took on the challenge to map the histological and ultrastructural landmarks of plaque vulnerability and associate these morphological characteristics with the corresponding site-specific cellular composition and transcriptome. Atherosclerotic plaques were subdivided in a proximal, most stenotic and distal part according to blood flow, and analyzed using histology, electron microscopy, RNAseq and spatial transcriptomics.  The proximal and most-stenotic parts of the plaque showed features of endothelial cell denudation and thrombosis, and on a transcriptomic level, the proximal and most-stenotic part of the atherosclerotic plaque were distinct from the distal part. These segments were more inflamed with increased macrophage, T-cell and NK cell signatures, and contained less vascular smooth muscle cells. Spatial transcriptomics revealed MMP9 to be differentially expressed in the area of plaque rupture and was co-expressed with macrophage and T cell markers. Moreover, the expression of MMP9 was higher in the shoulder region of symptomatic vs asymptomatic patients, and MMP9 levels in the most stenotic segment of the plaque was associated with a greater risk for future cardiovascular events. 

The paper of the Goncalves laboratory highlights the importance of geographic mapping of biological features of atherosclerotic plaques, thereby paving the way for the discovery and development of site-specific therapeutics to prevent atherosclerotic plaque rupture.