Background and Purpose：Hypoxia, as a risk factor for pulmonary hypertension (PH), was an inducing factor for pulmonary artery endothelial cells (PAECs) injury and inflammation. Pyroptosis induced cell death along with the maturation and secretion of the inflammatory mediators. However, the correlation among pyroptosis, PAECs injury and inflammation remain unknown. Here, we explored, in detail, the effect of hypoxia on pyroptosis of PAECs. Experimental approach：Using RNA-seq sequencing method, we screened differentially expressed genes in pulmonary artery in SU5416-induced hypoxia PH model. Next, we verified the role and mechanism of the differentially expressed gene GPR146 in PAECs by immunohistochemistry, immunofluorescence, CCK8, western blotting, realtime PCR, and LDH release experiments. Key Results: Our results showed that GPR146 was highly expressed in PH human lung tissue and Sugen5416/hypoxia (SuHx) induced rat PAH lung tissues. Meanwhile, our data suggested the expression of pyroptosis-related proteins was remarkably increased under hypoxia both in vivo and in vitro, which were inhibited by silencing GPR146. Moreover, inhibiting NLRP3 or caspase-1 effectively suppressed cleavage of caspase-1, production of interleukin (IL)-1β and IL-18 in PAECs by hypoxia and overexpression of GPR146. Conclusion and Implications: Our results indicated that GPR146 induced pyroptosis and inflammatory responses through the NLRP3/caspase-1 signaling axis, triggering endothelial injury and vascular remodeling. Hypoxia could promote PAECs pyroptosis through upregulation of GPR146 to affect the progression of PH, which might provide novel targets for treatment of PH.