Atherosclerosis is the leading cause of cardiovascular disease worldwide. In atherosclerosis, smooth muscle cells (SMCs) accumulate in the intima where they undergo a transition from a contractile to a synthetic phenotype. During the two last decades, synthetic SMCs have been considered as beneficial players in atherosclerotic plaque development by essentially contributing to fibrous cap formation that protects plaque from rupture. However, SMCs exhibit a remarkable plasticity, and recent studies have demonstrated that a high proportion of SMCs in atherosclerotic plaques are hardly detectable with the classical SMC markers and acquire proinflammatory macrophage-like phenotype. We have previously identified S100A4 as a marker of the synthetic phenotype, both in vitro and in vivo in pigs and humans. The main project of this thesis aimed at deciphering the role of extracellular S100A4 in phenotypic transition of SMCs and atherosclerotic plaque progression. Our results indicated that extracellular S100A4 is causally related to atherosclerotic plaque progression, putting it forward as a prospective therapeutic target for plaque stabilization and/or regression.