Dual Lineage Tracing Identifies Cellular Mechanisms Underlying Radiation-Associated Changes in Atherosclerotic Lesion...

Area of Science:

• Vascular Biology
• Atherosclerosis Research
• Cellular Plasticity

Background:

• Phenotypic plasticity of smooth muscle cells (SMCs) and endothelial cells (ECs) impacts atherosclerotic plaque stability.
• Understanding how these cells interact under vascular stress like irradiation is limited.
• Simultaneous fate mapping of both cell types in lesions has been a major challenge.

Purpose of the Study:

• To develop and utilize a dual lineage tracing model for simultaneous fate mapping of SMCs and ECs.
• To investigate the coordinated responses of SMCs and ECs under irradiation and Western diet-induced atherosclerosis.
• To identify cell dynamics contributing to plaque instability after irradiation.

Main Methods:

• Generation of dual lineage tracing Apoe-deficient mice for simultaneous SMC and EC fate mapping.
• Induction of atherosclerosis via irradiation and Western diet.
• Analysis using lineage tracing, immunostaining, and single-cell RNA sequencing.

Main Results:

• Irradiation caused SMC-derived cells to reduce lesion investment and upregulate inflammatory genes.
• EC-derived cells expanded and expressed SMC-associated genes post-irradiation.
• Lesions showed reduced collagen and fewer ACTA2+ cells in the fibrous cap, indicating decreased stability.

Conclusions:

• Dual lineage tracing confirmed irradiation-induced SMC loss and EC expansion are not artifacts.
• Irradiation triggers inflammatory reprogramming of SMCs and phenotypic modulation of ECs.
• These cellular changes, including impaired matrix organization, may increase atherosclerosis risk after radiotherapy.