Ubiquitin-proteasome system (UPS) is considered to be the key regulator in protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor that is approved by FDA for the treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ has been reported to be effective against the pulmonary vascular characteristic associated with chronic hypoxia- and monocrotaline(MCT)-induced pulmonary hypertension. However, the underlying detailed mechanisms remains poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca²⁺ concentration ([Ca²⁺]_i) and store-operated Ca²⁺ entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) involve in the pulmonary vascular remodeling process. In this study, we investigated the effects of BTZ on proliferation as well as [Ca²⁺]_i, especially the process of SOCE, and a list of SOCE-related regulatory proteins such like HIF-1α, BMP4, PPAR, TRPC1 and TRPC6 in rat distal PASMCs. Results showed that: 1) In either hypoxia-induced or MCT-induced rat PH models, BTZ markedly attenuated the elevated right ventricular pressure, right ventricular hypertrophy and pulmonary vascular remodeling; 2) BTZ prevented the process of PH by inhibiting hypoxia-increased cell proliferation, basal [Ca²⁺]_i and SOCE in PASMCs; 3) BTZ also significantly normalized the hypoxia-upregulated HIF-1α, BMP4, TRPC1 and TRPC6 expression and the downregulated PPAR expression in distal pulmonary arteries (PAs) and PASMCs. These results indicated that BTZ exerts its protective role in the development of PH likely by inhibiting the TRPC-SOCE-[Ca²⁺]_i signaling axis in PASMCs.