Decoding the transcriptome of calcified atherosclerotic plaque at single-cell resolution

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Systems Biology

Background:

• Atherogenesis is a complex process involving inflammation, tissue remodeling, and cellular transdifferentiation (CTD), making its pathophysiology challenging to understand.
• Existing research often overlooks the distinct cellular behaviors within different anatomical regions of atherosclerotic plaques.

Purpose of the Study:

• To delineate the pathophysiology of atherogenesis by analyzing transcriptional profiles of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs).
• To identify region-specific cellular functions and potential drivers of cellular transdifferentiation (CTD) within atherosclerotic plaques.

Main Methods:

• Single-cell RNA sequencing was employed to analyze transcriptional profiles of VSMCs and ECs.
• Systems-biology approaches were used to analyze data from carotid artery tissue, comparing calcified atherosclerotic core (AC) plaques with proximal adjacent (PA) regions.

Main Results:

• Anatomical distinction observed: PA cells express inflammatory mediators, while AC cells predominantly express matrix-secreting genes.
• Tumor necrosis factor-alpha (TNFa) signaling identified as a potential driver of inflammation in PA ECs and VSMCs.
• Candidate drivers of CTD in AC VSMCs (POSTN, SPP1, IBSP) and AC ECs (ITLN1, SCX, S100A4) were identified.

Conclusions:

• Established an anatomical framework for understanding atherogenesis, highlighting distinct cellular roles in different plaque regions.
• Findings provide a basis for exploring site-specific strategies to disrupt atherosclerotic disease progression.
• Identified specific genes as potential therapeutic targets for cellular transdifferentiation in the atherosclerotic core.