Molecular mechanism of the signaling pathways that induce dedifferentiation of smooth muscle cells

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The phenotypic modulation of vascular smooth muscle cells (SMCs) from the differentiated state to the dedifferentiated one is critical event in the development and progression of atherosclerosis. However, the critical atherogenic factors remain unclear. We established primary culture systems for visceral and vascular SMCs in which both SMCs can maintain a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level expression of SMC differentiation markers. In this study, we searched for critical SMC dedifferentiation factors using our culture systems. We found that polar lipids extracted from human serum markedly induced SMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several LPA species detected in human serum lipids, unsaturated LPAs were identified as major contributors for SMC dedifferentiation. Unsaturated (18:1) LPA, but not saturated (18:0) LPA, strongly induced vascular SMC dedifferentiation in culture and vascular remodeling consisted of neointima in rat carotid arteriesin vivo. 18:1 LPA-induced vascular SMC dedifferentiation in culture and vascular remodelingin vivo were mediated through the coordinated activation of both ERK and p38 MAPK. The neointima was mainly derived from dedifferentiated medial vascular SMCs. During 18:1 LPA-induced vascular remodeling, the phenotypic modulation of medial vascular SMCs preceded macrophage infiltration. Thus, this study demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce vascular SMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.