PCSK9 in vascular smooth muscle cells: biology, pathology, and inhibition to fight atherosclerosis

Atherosclerosis remains the principal cause of cardiovascular morbidity and mortality worldwide, with vascular smooth muscle cells (VSMC) serving as central effectors in plaque initiation, progression, and destabilization. Although originally characterized as a hepatic regulator of LDL receptor degradation and systemic cholesterol homeostasis, PCSK9 is increasingly recognized as a pivotal mediator of vascular pathology. Within the arterial wall, VSMC constitute the predominant extrahepatic source of PCSK9, through which it exerts autocrine and paracrine effects on proliferation, migration, phenotypic plasticity, foam cell formation, oxidative stress, inflammation, and calcification. Collectively, these processes destabilize vascular homeostasis and amplify maladaptive crosstalk with endothelial and immune cells, thereby accelerating atherogenesis. Therapeutic inhibition of PCSK9 provides benefits beyond lipid lowering, reinforcing fibrous cap stability, and dampening inflammatory activity within plaques. While monoclonal antibodies and RNA-based silencing therapies are supported of a growing body of clinical data, recent advances include the development of novel oral PCSK9 inhibitors, among which MK-0616 (Enlicitide) has progressed to phase 3 evaluation. Conversely, genome editing, peptide vaccination, and CAP1-targeted biologics remain at a conceptual or early investigational stage and are still distant from regulatory approval. Yet PCSK9 lives a double life: circulating as a systemic regulator of lipids while acting locally as a driver of vascular pathology. Unraveling this duality through focused research is essential to unlock its full potential in cardiovascular medicine. • VSMC are the main extrahepatic source of arterial PCSK9. • PCSK9 disrupts VSMC homeostasis via NF – kB reciprocal activation. • PCSK9 reprograms VSMC, promoting pro-atherogenic pathways. • PCSK9 enhances pathological crosstalk with endothelial and immune cells. • PCSK9 inhibition thickens fibrous caps and stabilizes plaques.