Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids

The phenotypic modulation of vascular smooth muscle cells (VSMCs) from the differentiated state to the dedifferentiated one is critically involved in the development and progression of atherosclerosis. Although many cytokines and growth factors have been reported as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because pro per examining systems of them have not been developed. We recently establis hed primary culture systems for visceral SMCs and VSMCs in which both SMCs, when cultured on laminin with insulin-like growth factor-I, show a differe ntiated phenotype, as indicated by a spindle-like shape, ligand-induced con tractility, and a high level of SMC differentiation marker gene expression. In this study, we searched for critical dedifferentiation factors for thes e SMCs using our culture system. We found that polar lipids extracted from human serum markedly induced VSMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several L PA species detected in human serum lipids, unsaturated LPAs were identified as major contributors to the induction of VSMC dedifferentiation. Signalin g and phenotype analyses revealed that unsaturated LPA-induced VSMC dediffe rentiation is mediated through the coordinated activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Thus, thi s report demonstrates the first finding that unsaturated LPAs, but not satu rated LPAs, specifically induce VSMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.