Abstract 1740: Lysophosphatidic Acid: a Two-Faced Key Actor in Atherogenesis
Lysophosphatidic acid (LPA) mediates multiple cellular processes that are instrumental in atherogenesis, including SMC contraction, platelet aggregation, apoptosis and immunity. For instance, LPA prevents T-cell apoptosis, regulates IL-2 secretion and stimulates adhesion of monocytes and neutrophils to endothelial cells. In addition, LPA regulates trafficking, cytokine production, and T cell-activation of dendritic cells and stimulates chemokine generation and histamine release by mast cells. Given its pleiotropic character we argued that the net effect of LPA on atherogenesis may be context dependent. In this study we determined the effect of systemic and focal exposure to LPA on atherogenesis. Atherosclerotic lesions were induced in ApoE−/− mice (n=6 per group) by perivascular carotid artery collar placement and LPA was administered either systemically (3 intraperitoneal injections of 50 μg/kg per week leading to an increase in plasma LPA levels of approximately 85 nM) for 4 weeks or perivascularly through a pluronic gel (20 μM) at the lesion site 5 weeks after surgery. Surprisingly, lesion analysis revealed a significant reduction in lesion size after systemic LPA treatment (56 ± 27*103 μm2 versus 103 ± 41*103 μm2 for PBS treated controls; P=0.037). Plaque morphology of LPA mice differed markedly from that of controls in terms of collagen (−75%; P=0.003) and ASMA positive vSMC content (+70%; P=0.028), while there was no effect on macrophage content. In sharp contrast, lesion size and macrophage, smooth muscle cell and collagen content remained unaffected after perivascular LPA exposure in advanced lesions. These lesions were characterized by an increased number of activated adventitial mast cells and a concomitant increased incidence of intraplaque hemorrhage (42% versus 10% for controls).In conclusion, LPA displays an intriguing dual effect on atherosclerosis in that systemic exposure attenuates plaque development in ApoE−/− mice and promotes a stable plaque phenotype, while conversely, acute focal exposure appears to have a destabilizing effect on advanced lesions possibly by activation of mast cells. Thus the net effect of LPA appears to depend on its source and context.