Smooth Muscle Cell-Derived Fibronectin Promotes an Atheroprotective Smooth Muscle Cell Phenotype Associated With...

Area of Science:

• Cardiovascular Biology
• Extracellular Matrix Research
• Atherosclerosis Pathogenesis

Background:

• Coronary artery disease (CAD) is a leading global cause of death, with atherosclerosis progression linked to smooth muscle cell (SMC) phenotypic switching.
• The role of extracellular matrix (ECM) components, such as fibronectin (Fn1), in regulating SMC behavior within atherosclerotic plaques remains incompletely understood.
• Fibronectin (Fn1) is abundant in atherosclerotic lesions and associated with human CAD risk.

Purpose of the Study:

• To investigate the functional role of SMC-derived fibronectin (Fn1) in regulating SMC phenotype and plaque stability during atherogenesis.
• To elucidate the molecular mechanisms by which Fn1 influences SMC behavior and its potential crosstalk with other CAD-associated pathways.

Main Methods:

• Utilized mouse genetic models for targeted ablation of SMC-derived Fn1.
• Employed single-cell analyses, cell lineage tracing, and immunostaining techniques.
• Examined both murine and human atherosclerotic lesions for comparative analysis.

Main Results:

• Genetic deletion of SMC-derived Fn1 reduced alpha smooth muscle actin-positive cells and collagen content, indicating decreased plaque stability.
• Plaques lacking SMC-derived Fn1 exhibited an increase in modulated SMCs with lower collagen expression and enhanced NO-cGMP pathway activity.
• Expression of Fn1 and NO-sensitive guanylyl cyclase (NO-GC) was observed in modulated SMCs within human atherosclerotic lesions.

Conclusions:

• SMC-derived Fn1 plays a crucial role in promoting atherosclerotic plaque stability by suppressing SMC phenotypes associated with instability.
• The atheroprotective effects of Fn1 may involve a crosstalk with the NO-cGMP signaling axis within SMCs.
• This study establishes a mechanistic link between the CAD risk genes Fn1 and NO-GC, clarifying how ECM regulates SMC phenotype and plaque stability.