Objective To investigate the role of the IP3R2/GRP75/VDAC1 axis in regulating mitochondrial calcium transport in apoptosis in an in vitro hypoxia-induced injury model of pulmonary artery smooth muscle cells (PASMCs). Methods Rat PASMCs were cultured in vitro and randomly divided into three groups: normal control group, hypoxia group, and a drug intervention group (4-Phenylbutyric acid). Intracellular, endoplasmic reticulum(ER), and mitochondrial Ca_²⁺ concentrations in PASMCs were measured using Ca_²⁺ fluorescent probes. Mitochondrial structure and morphological changes were observed by transmission electron microscopy. Cell apoptosis was detected by flow cytometry. The mRNA and protein expression levels of key factors in the Ca_²⁺ pathway and mitochondrial fission and fusion were determined by RT-qPCR and Western blot, respectively. Results In the hypoxia-induced injury model, the concentrations of Ca₂₊ ^{in the} ER and cytoplasm of PASMCs increased, while the mitochondrial Ca₂₊ concentration decreased (P<0.01). Mitochondria exhibited reduced volume, swelling, disordered cristae structure, and increased rupture; PASMC apoptosis decreased (P< 0.01). The mRNA and protein expression levels of key Ca_²⁺ transport pathway factors IP3R2, GRP75, and VDAC1 were upregulated (P<0.01), as was the expression of the mitochondrial fission factor DRP1 (dynamin-related protein 1) (P<0.01), while the expression of the mitochondrial fusion factor MFN2 (mitofusin-2) was downregulated (P<0.01). After intervention with 4-PBA, compared to the hypoxia group, the concentrations of Ca₂₊ ^{in the} ER and cytoplasm of PASMCs decreased, while mitochondrial Ca₂₊ ^{concentration increased (}P<0.05). Mitochondrial structure was restored, and the expression of IP3R2, GRP75, VDAC1, and DRP1 decreased, while MFN2 expression increased, with an increase in PASMCs apoptosis. Conclusion The IP3R2/GRP75/VDAC1 axis enhances mitochondrial Ca₂₊ ^{transport in hypoxia-induced PASMCs,} promoting PASMCs apoptosis, and provides a theoretical basis for the prevention and treatment of HPH.