Lysophosphatidic acid acts on LPA1 receptor to increase H2O2 during flow-induced dilation in human adipose arterioles

BACKGROUND AND PURPOSE NO produces arteriolar flow-induced dilation (FID) in healthy subjects but is replaced by mitochondria-derived hydrogen peroxide (mtH(2)O(2)) in patients with coronary artery disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH(2)O(2) in human visceral and subcutaneous adipose arterioles. EXPERIMENTAL APPROACH Arterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L-NAME) or H2O2 scavenging (Peg-Cat) +/- LPA (10 mu M, 30 min), +/- LPA(1)/LPA(3) receptor antagonist (Ki16425) or LPA(2) receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells. KEY RESULTS FID was inhibited by L-NAME but not Peg-Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg-Cat while L-NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA(1) and LPA(2) but not LPA(3) receptors were detected in arterioles. LPA(1) but not LPA(3) receptor protein was detected by Western blot. Pretreatment of vessels with an LPA(1)/LPA(3), but not LPA(2), receptor antagonist prior to LPA preserved NO-mediated dilation. CONCLUSIONS AND IMPLICATIONS These findings suggest an LPA(1) receptor-dependent pathway by which LPA increases arteriolar release of mtH(2)O(2) as a mediator of FMD.