Neointimal lesions are characterized by accumulation of cells within the arterial
wall and are a prelude to atherosclerotic disease. Here we report that a brief exposure
to either alkyl ether analogs of the growth factor-like phospholipid lysophosphatidic
acid (LPA), products generated during the oxidative modification of low density lipoprotein,
or to unsaturated acyl forms of LPA induce progressive formation of neointima in vivo
in a rat carotid artery model. This effect is completely inhibited by the peroxisome
proliferator-activated receptor (PPAR)gamma antagonist GW9662 and mimicked by PPARgamma
agonists Rosiglitazone and 1-O-hexadecyl-2-azeleoyl-phosphatidylcholine. In contrast,
stearoyl-oxovaleryl phosphatidylcholine, a PPARalpha agonist and polypeptide epidermal
growth factor, platelet-derived growth factor, and vascular endothelial growth factor
failed to elicit neointima. 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 G protein-coupled receptor activation. Neointima-inducing LPA analogs
up-regulated the CD36 scavenger receptor in vitro and in vivo and elicited dedifferentiation
of cultured vascular smooth muscle cells that was prevented by GW9662. These results
suggest that selected LPA analogs are important novel endogenous PPARgamma ligands
capable of mediating vascular remodeling and that activation of the nuclear transcription
factor PPARgamma is both necessary and sufficient for neointima formation by components
of oxidized low density lipoprotein.
