LPA receptor 4 deficiency attenuates experimental atherosclerosis.

The widely expressed lysophosphatidic acid (LPA) selective receptor 4 (LPAR4) contributes to vascular development in mice and zebrafish. LPAR4 regulates endothelial permeability, lymphocyte migration, and hematopoiesis, which could contribute to atherosclerosis. We investigated the role of LPAR4 in experimental atherosclerosis elicited by adeno-associated virus expressing PCSK9 to lower LDL receptor levels. After 20 weeks on a Western diet, cholesterol levels and lipoprotein distribution were similar in WT male and Lpar4 mice (P = 0.94). The atherosclerotic lesion area in the proximal aorta and arch was ∼25% smaller in Lpar4 mice (P = 0.009), and less atherosclerosis was detected in Lpar4 mice at any given plasma cholesterol. Neutral lipid accumulation in aortic root sections occupied ∼40% less area in Lpar4 mice (P = 0.001), and CD68 expression was ∼25% lower (P = 0.045). No difference in α-smooth muscle actin staining was observed. Bone marrow-derived macrophages isolated from Lpar4 mice displayed significantly increased upregulation of the M2 marker Arg1 in response to LPA compared with WT cells. In aortic root sections from Lpar4 mice, heightened M2 "repair" macrophage marker expression was detected by CD206 staining (P = 0.03). These results suggest that LPAR4 may regulate the recruitment of specific sets of macrophages or their phenotypic switching in a manner that could influence the development of atherosclerosis.

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