Single-Cell Spatial Transcriptomics Reveals Sex-Specific Differences Driving Carotid Atherosclerotic Plaque...

Area of Science:

• Cardiovascular Biology
• Immunology
• Genomics

Background:

• Ischemic stroke is a major cardiovascular disease, with carotid atherosclerotic plaques contributing significantly.
• Sex differences impact plaque composition and patient outcomes post-stroke.
• Males develop more unstable plaques, while females experience worse post-stroke outcomes.

Purpose of the Study:

• To investigate sex-specific cellular and molecular mechanisms underlying carotid plaque instability.
• To identify distinct pathways driving plaque destabilization in males versus females.

Main Methods:

• Single-cell RNA sequencing of over 64,000 cells from male and female carotid endarterectomy specimens.
• Integration of single-cell RNA sequencing with high-plex spatial transcriptomics (CosMx) for cellular localization.
• Analysis of cell-cell interactions and gene expression within key histological regions.

Main Results:

• Vascular smooth muscle cells (VSMCs), T lymphocytes, and macrophages constitute ~88% of plaque cells.
• Male unstable plaques show reduced contractile VSMCs and increased inflammatory VSMCs and macrophages.
• Female unstable plaques have more cytotoxic T lymphocytes and foam-cell macrophages, with distinct spatial distribution of VSMCs in males.

Conclusions:

• Distinct cellular and spatial mechanisms contribute to plaque destabilization in males and females.
• Findings highlight the need for sex-specific diagnostic and therapeutic strategies for carotid atherosclerosis.
• Sex-specific approaches are essential for managing cardiovascular disease risk associated with plaque instability.