|Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2002: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2001: ¥10,300,000 (Direct Cost: ¥10,300,000)
The phenotypic modulation of vascular smooth muscle cells (SMCs) from the differentiated state to the dedifferentiated one, which results in cell proliferation and migration, is a hallmark of the development and progression of atherosclerosis. Although many cytokines and growth factors have been proposed as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because proper examining systems of them have not been developed. We recently established primary culture systems for vascular SMCs in which SMCs, when cultured on laminin with insulin-like growth factor-1, show a differentiated phenotype as indicated by a spindle-like shape, ligand-induced contractility, and high levels of SMC differentiation marker gene expression.
Using our culture system, we investigated the signaling pathways affecting the vascular SMC phenotype, and found that the IGF-1-stimulated phosphoinositide 3-kinase (P13-K)/protein kinase B (PKB(Akt)) pathway plays a critical
role in maintaining a differentiated phenotype and the coordinated activation of the extracellular-signal regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) pathways by growth factors and cytokines induces dedifferentiation. Thus, changes in the balance between the strengths of the P13-K/PKB (Akt) pathway and the ERK and p38MAPK pathways would determine the phenotype of vascular SMCs.
Using our culture system of vascular SMCs, we searched for critical dedifferentiation factors and identified that lysophosphatidic acids (LPAs) in human serum potently induce SMC dedifferentiation. Among several LPA species detected in human serum polar lipids, unsaturated LPAs were major contributors to induce vascular SMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced vascular SMC dedefferentiation also mediates through the coordinated activation of ERK and p38MAPK. Furthermore, naturally occurring unsaturated, but not saturated, LPAs strongly induced neointimal formation in rat carotid arteries in vivo.
Our study demonstrates the vascular remodeling in vivo triggered by naturally occurring unsaturated LPAs and provides a novel pathogenic animal model for atherogenesis. Less