Single-Cell RNA-Seq Reveals Adventitial Fibroblast Alterations during Mouse Atherosclerosis.

Area of Science:

• Vascular Biology
• Genomics
• Cardiovascular Research

Background:

• Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death, necessitating novel lipid-independent therapies.
• Genome-wide association studies (GWAS) implicate vascular cell genes in ASCVD, suggesting therapeutic targets within the vessel wall.
• The adventitial layer of vasculature and its cells are increasingly recognized for their role in potentiating ASCVD.

Purpose of the Study:

• To investigate the role of adventitial cells in atherosclerosis.
• To identify regulators of adventitial responses in ASCVD by integrating single-cell RNA sequencing with human GWAS data.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of aortic adventitia in male Ldlr-/- mice during atherogenesis.
• Cross-referencing scRNA-seq data with human ASCVD GWAS findings.
• In vitro validation of identified regulators in human adventitial fibroblasts.

Main Results:

• Identified four distinct adventitial fibroblast populations with dynamic shifts in size and gene expression during atherogenesis.
• Discovered differential expression of SERPINH1, a GWAS-implicated gene, in adventitial fibroblasts.
• In vitro SERPINH1 knockdown reduced fibroblast migration and altered gene expression.

Conclusions:

• Adventitial fibroblasts undergo dynamic changes during atherosclerosis.
• Reduced SERPINH1 expression impairs adventitial fibroblast function.
• These disruptions contribute to the progression of atherosclerotic cardiovascular disease (ASCVD).