Atherosclerosis is the leading cause of death in the United States and the cause of more than half of all mortality in the world's developed countries. Neointimal lesions are characterized by accumulation of cells within the arterial wall and are a prelude to atherosclerotic disease that can lead to heart attack and stroke. Our preliminary data have demonstrated that a brief exposure to select forms of the lysophospholipid growth factor lysophosphatidic acid (LPA, 1-radyl-2- lyso-sn-3-glycero-3-phosphate) cause profound vascular remodeling. LPA and select LPA analogs cause progressive neointima formation in rat and mouse carotid arteries and the phenotypic dedifferentiation of vascular smooth muscle cells (VSMC) in vitro. LPA-induced vascular remodeling occurs in the physiological concentration range (1-10 mu/M) without prior mechanical damage to or removal of the endothelial cells from the carotid artery. Many of the growth factor-like effects of LPA are mediated through specific G protein-coupled receptors (GPCR). Recently, LPA has been identified as an agonist of the peroxisome proliferator-activated receptor gamma (PPARgamma), a lipid-activated nuclear transcription factor. We found that LPA-induced neointima formation and VSMC transdifferentiation are mimicked by the PPARgamma agonists and that these responses are completely inhibited by pretreatment with the PPARgamma antagonist GW9662. The structure-activity relationship for neointima induction by LPA analogs in vivo is identical to that of PPARgamma activation in vitro and disparate from that of LPA GPCR. Inhibitors of LPA GPCR slightly attenuated but did not prevent neointima formation. Based on these observations we propose to test the hypothesis that select molecular forms of LPA are novel endogenous PPARgamma ligands capable of evoking vascular remodeling and that activation of the nuclear transcription factor PPARgamma is both necessary and sufficient for neointima formation. We propose to: 1. Determine whether genetic deletion of the LPA, or LPA2 or both GPCR renders mice resistant to LPA-induced neointima formation and prevents phenotypic transdifferentiation of VSMC 2. Determine whether conditional genetic deletion of PPARgamma, targeted to endothelial and/or vascular smooth muscle cells and/or macrophages, renders mice resistant to LPA-induced neointima formation and in VSMC prevents phenotypic transdifferenatiation. The proposed studies will provide entirely new knowledge by identifying which LPA receptor(s) mediating vascular remodeling and neointima formation, thus pinpointing a novel target for the prevention of atherogenesis. We will obtain new insights into the pathophysiological role of PPARgamma in vascular remodeling. Furthermore, we will break new grounds in LPA biology by conclusively demonstrating its role not only as a GPCR ligand but also as a transcellular mediator, a novel endogenous ligand of PPARv that is capable of causing vascular remodeling.
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