The pathogenesis of pulmonary arterial hypertension (PAH) and the associated endothelial dysfunction is complex. Oxidative stress and dysfunctional signaling through bone morphogenic protein receptor type 2 (BMPR2) have been shown to be central pathogenic mechanisms in PAH. We have previously shown that relative expression level of the G-protein coupled receptor GPR55 exerts a significant modifier effect on the penetrance of BMPR2 mutations in heritable PAH in humans. We have also previously reported that levels of isofurans – products of free radical lipid peroxidation – are significantly elevated in PAH, and that stimuli that increase oxidative stress and isofuran production in the murine lung – namely, brief daily hyperoxia – enhance the development of PAH as well. We thus initially hypothesized that GPR55 might be regulated by oxidative stress. Consistent with this hypothesis, we found that GPR55 is upregulated in the murine lung following hyperoxia (average 5.2-fold increase). However, GPR55 was also found to be upregulated in the lungs of mice treated with Sugen/hypoxia (average 1.9-fold increase), a condition that disfavors isofuran formation. Oxidative stress and hypoxia will both independently stabilize and activate hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2). In human lung endothelial cells, treatment with dimethyloxalylglycine (DMOG) or CoCl2, chemical inducers of HIF1 and HIF2 that work via inhibition of 2-oxoglutarate dependent oxygenases (2OGDOs), dose-dependently increased GPR55 by Western blot (1.2-fold increase at 0.1mM DMOG up to 6.2-fold increase with 1mM DMOG). Timecourse experiments revealed that GPR55 increased with kinetics similar to that of HIF-1, suggesting direct regulation of GPR55 by 2OGDOs as opposed to regulation by HIF (which would require a time lag for gene transcription and new protein synthesis). GPR55 thus appears to be a novel GPCR involved in the pathogenesis of pulmonary vascular disease and PAH through HIF-independent, but 2OG-dependent injury response pathways.