Fig. 1.

Role of bioactive lipids in vascular tone. AA is formed via PLA₂, which can subsequently be converted to a HETE (via LOX), an EET (via CYP-450), or to PGI₂ (via COX2). EETs can be further metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). AA derivatives are capable of causing either smooth muscle cell relaxation or constriction, depending on specific isoform and concentration. Ceramide, formed by NSmase, promotes H₂O₂-dependent flow-induced dilation (FID). However, if hydrolyzed to sphingosine by NCdase, it can be further converted to S1P, which promotes NO-dependent FID. Alternatively, S1P can transport to the extracellular space, where it can bind to S1PRs. Activation of S1PR results in SMC relaxation and vasodilation. PA and PC can be converted to LPA by PLA and lyso-PLD. Atx converts LPC to LPA, which then can activate LPARs, or, be degraded by LPP3 to form MAG. Downstream signaling from LPARs promotes H₂O₂-dependent FID in the microcirculation. AA,  arachidonic acid; Atx, autotaxin; HETE, hydroxyeicosatetraenoic acid; LPAR, lysophosphatidic acid receptor; LPP3, lipid phosphate phosphatase 3; COX₂  cyclooxygenase 2; CYP-450, cytochrome-P450; EETs, epoxyeicosatrienoic acids; LOX, lipoxygenase; LPA,  lysophosphatidic acid; LPC, lysophosphatidylcholine; Lyso-PLD, lysophospholipase D; MAG, monoacylglycerol; NCdase, neutral ceramidase; NO, nitric oxide; NSmase, neutral sphingomyelinase; PA, phosphatidic acid; PC, phosphatidylcholine; PGI₂, prostacyclin; PLA, phospholipase; SMC, smooth muscle cell; S1P, sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate receptor.