Objective – The endocannabinoid system regulates stress, food intake and emotional behavior. Endocannabinoids are also beneficial in the cardiovascular system as they reduce blood pressure and infarct size. Whether endocannabinoids , however, also have anti-inflammatory functions is controversial. We therefor set out to identify the impact of endocannabinoids on inflammatory signaling in vascular cells. Results – Anandamide (AEA), the ethanolamide of arachidonic acid, is one of the best-characterized endocannabinoids. We therefore focused on this compound. Pretreatment of murine and human aortic smooth muscle cells (hSMCs) with AEA decreases the Interleukin- 1β – and Tumor necrosis factor α- induced upregulation of inflammatory genes (e.g. CCL2) on mRNA and protein level. These effects were not mediated by peroxisome proliferator-activated receptors (PPARs) or the classic cannabinoid receptors CB1 or CB2 and are therefore potentially mediated by intracellular cannabinoid receptors. RNA sequencing data revealed a massive upregulation of the nuclear receptor family NR4A in response to AEA. Knockdown of NR4A by lentiviral CRISPR/ Cas9 in SMC blocked the anti-inflammatory effect of AEA. Similarly, overexpression of NR4A in HEK cells could promote the effect anti-inflammatory effect of the endocannabinoid. In line with this, reportergen assay carrying the NR4A binding motifs demonstrated that AEA promoted NR4A recruitement to the construct and this resulted in inhibition of transcription. Thus, we suggest that AEA treatment activates NR4A receptors and promotes their interaction with nuclear corepressors. Indeed, chromatin immune-precipitation experiments in vascular cells show that the endocannabinoid treatment results in increased formation of heterochromatin at the promoter of the important inflammatory cytokine CCL2 promoter. Such a formation of heterchromatin is often a consequence of the recruitment of corepressors. Conclusions – AEA reduces the inflammatory response of vascular SMC by epigenetic silencing of inflammatory genes. This is mediated by activation of NR4A and their recruitment of nuclear corepressors. .