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LPA‐induced activation of LPA1 receptor leads to the loss of NO‐mediated flow‐induced dilation in human microvessels

Flow‐induced dilation (FID) in arterioles from patients with coronary artery disease (CAD) is dependent on hydrogen peroxide (H2O2) rather than the nitric oxide (NO)‐mediated mechanism observed in arterioles from patients without CAD. Circulating levels of lysophosphatidic acid (LPA), a bioactive lipid, range from low to high nanomolar levels in healthy individuals, but increase to micromolar levels in patients with risk factors for CAD as well as early and advanced stages of atherosclerosis. Studies from our laboratory show that acute (30 min) exposure to 10μM LPA in vessels from patients without CAD shifts the mediator of FID from NO to H2O2, recapitulating the CAD phenotype. LPA effects are mediated through cognate LPA receptors, but it is unknown which receptors are expressed in human arterioles and may be responsible for the observed LPA‐induced shift in the mediator of FID. Based on our observed expression pattern of LPA receptors in human arterioles, we hypothesized that LPA‐induced switch to H2O2 as the mediator of FID is mediated by LPA1 receptor, and the shift can be prevented by blocking the receptor prior to LPA challenge.