The nuclear receptor family of ligand activated transcription factors constitutes 48 members in man (1). We and others have shown that the blood vessel wall and its vascular smooth muscle and vascular endothelial cell components contain a wide variety of nuclear receptors including members of the retinoic acid receptor, retinoid X receptor, farnesoid X receptor, pregnane X receptor, and peroxisome proliferator-activated receptors (PPAR)–α, -β/δ and –γ families. In recent years, in particular PPARα and PPARγ have been the focus of much attention since they are the molecular targets for the clinically used lipid lowering fibrate and the insulin sensitising glitazone classes of drugs respectively (2). Moreover, PPARα and PPARγ ligands are anti-inflammatory and anti-proliferative in vascular cells and inflammatory cells, and have been shown to reduce atherosclerosis in animal models and reduce restenosis after balloon angioplasty in animal models and in patients. At the same time there has been a great interest in the potential endogenous ligands for PPARs, which have been suggested to be a variety of lipids, oxidised lipids, eicosanoids, and a number of polyunsaturated fatty acids (2). The PPARs are activated by a wide variety of lipids at a relatively low affinity, which has led to the suggestion that they may be general lipid sensing transcription factors within the body. However, recent data suggests that potent high affinity PPAR ligands may also exist formed from arachidonic acid. Arachidonic acid is metabolised into a group of diverse highly active lipid mediators by 3 major pathways: the cyclo-oxygenase pathway producing predominantly prostanoids, the lipoxygenase pathways producing leukotrienes, HETEs and HODEs, and the epoxygenase pathway. Eicosatrienoic acids (EET)s are a group of short lived arachidonic acid metabolites produced by this cytochrome P450 epoxygenase pathway (3). A number of EETs and EET-metabolites can activate PPARα (4) and PPARγ (5). Furthermore, EETs released by vascular endothelial cells in response to flow are anti-inflammatory at least in part by activating PPARγ (5). Little is known however, regarding the enzymic source of these epoxygenase products. CYP2J2 is a vascular and pulmonary epoxygenase that is known to produce anti-inflammatory and anti-proliferative mediators (3). We have found that CYP2J2 activates all the PPARs and in particular PPARα. CYP2J2 activation of PPARα is anti-inflammatory, and anti-proliferative in vitro. In addition to vascular tissue, monocytes also contain CYP2J2 and when endogenous epoxygenases are inhibited, a role for CYPs in the tonic suppression of monocyte/ macrophage activation is revealed. PPARα is also known to mediate the metabolic response to fasting, by in part inducing pyruvate dehydrogenase kinase-4. In vivo in the hearts of cardiac-specific CYP2J2 transgenic mice, we found that the presence of CYP2J2 selective augments the PPARα dependent induction of pyruvate dehydrogenase kinase-4 in response to fasting. This data with that of others suggests that local epoxygenase’s in particular CYP2J2 may be an important source of PPAR ligands. In conclusion, nuclear receptors play an important function in regulating vascular function. In particular recent evidence points to a protective role in vascular cells for the lipid sensing nuclear receptors PPARα and PPARγ. We have found that at least one epoxygenase, CYP2J2 is an excellent source of PPAR ligands. The epoxygenase enzyme family by making short lived mediators in the blood vessel wall may therefore provide a critical link between lipid sensing and transcriptional control.