Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine
protease that plays multiple biological functions in the regulation of physiological and
pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level
with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing
evidence shows that the direct impact of PCSK9 on the vascular wall also plays
an important role in atherosclerotic progression. Compared with other vascular cells, a
large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC).
Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as
phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification
of VSMC, helps us better understand the “pleiotropic” effects of VSMC on the
atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling
VSMC functions in vivo is far from enough. This review aims to holistically
evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting
VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic
understanding of PCSK9 effects on VSMC will further underpin the success of a
new therapeutic strategy targeting AS.