Cardiovascular disease is still the leading cause of death worldwide, comprising, among others, coronary heart disease, cerebrovascular disease, and peripheral arterial disease. The main cause for cardiovascular disease is atherosclerosis, which develops over decades in the intima of medium and large arteries. Smooth muscle cells (SMCs) play major roles during the development of atherosclerosis, where they are known to migrate from the media and accumulate in the intima, undergoing a transition from contractile to synthetic phenotype. This process is characterized by cell dedifferentiation, which is accompanied by an alteration in the expression of contractile proteins, as well as an increased production of extracellular matrix components. For the last three decades, synthetic SMCs have been addressed as beneficial players since their role in atherosclerosis was to contribute to the fibrous cap formation and prevent plaque rupture. However, this notion has been changing. Thanks to the implementation of cellular lineage-tracing techniques both in mouse (Cre-Lox system) and in human (epigenetic markers), it has been shown that SMCs dedifferentiate towards several distinct phenotypes. Some of them retain the SMC-lineage identity (therefore easily identified), while others lose it almost completely and start expressing markers typical of different cell lineages (e.g. foam cell-like, macrophage-like, and chondrocyte-like). Therefore, there is still a need for specific marker(s) of the synthetic/dedifferentiated phenotypes. Our group previously identified S100A4 as a marker of the synthetic phenotype, both in vitro and in vivo, in mouse, pig and human. This small calcium-binding protein exhibits intra‐ and extracellular functions, which are not fully understood. The aim of my project was to investigate and shed some light on the role of S100A4 in SMC phenotypic transition and atherosclerosis.