The role of caveolin-1 in atherosclerosis and its molecular mechanism

Atherosclerosis (AS), the fundamental pathological basis of most cardiovascular diseases, is a chronic and progressive inflammatory disorder characterized by lipid deposition and plaque formation within the arterial wall. Despite significant advances in pharmacological and interventional therapies, the global burden of AS remains substantial, emphasizing the need to identify novel molecular regulators and therapeutic targets. Caveolin-1 (Cav-1), a key scaffolding protein of plasma membrane caveolae, has emerged as a context-dependent modulator of lipid handling and vascular homeostasis in AS. Evidence from experimental and clinical studies indicates that Cav-1 participates in endothelial low-density lipoprotein (LDL) transcytosis and barrier function in endothelial cells (ECs), regulates cholesterol efflux and inflammatory signaling in macrophages (MΦs), and influences phenotypic plasticity in vascular smooth muscle cells (VSMCs). These coordinated actions position Cav-1 at the intersection of lipid metabolism and vascular inflammation. Notably, while global Cav-1 deficiency markedly attenuates atherosclerotic lesion formation in animal models, the cell type-specific and stage-dependent mechanisms underlying these effects remain incompletely understood. Cav-1 activity is further modulated by post-translational modifications (PTMs), particularly tyrosine-14 phosphorylation, which can influence its membrane localization, stability, and protein-protein interactions. In addition, emerging evidence suggests dynamic interplay between Cav-1 and autophagy-related pathways, highlighting its role in maintaining lipid and cellular homeostasis under metabolic stress. In this review, we systematically summarize current evidence regarding Cav-1 and caveolae across vascular cell types, delineate existing controversies and knowledge gaps, and evaluate the translational potential of targeting Cav-1-associated lipid regulatory pathways in AS.