Pulmonary hypertension (PH) is a common and devastating lung disease. The current primary medications for this disease are to use non-specific vasodilators, but patients do not always respond well to non-specific vasodilators. Voltage-dependent potassium channels and store-operated calcium channels may increase intracellular calcium concentration ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) to mediate the development of PH; however, experimental findings are uncertain. In a series of studies, we have explored the potential important role of ryanodine receptor 2 (RyR2) Ca2+ release channel in PH and its inhibition as therapeutic strategies for this disease. Our findings reveal that Rieske iron-sulfur protein (RISP) serves as a primary molecule to increase mitochondrial reactive oxygen species (ROS) generation, disassociate FKBP12.6 from RyR2, enhance the channel activity, and then induces calcium release from the sarcoplasmic reticulum (a major intracellular Ca2+ store), hereby causing PA vasoconstriction, remodeling, and ultimately hypertension. Moreover, the increased RISP-dependent ROS can also cause DNA damage to activate ataxia telangiectasia mutated (ATM) kinase, phosphorylate checkpoint kinases 2 (Chk2), and cause cell proliferation in PASMCs, leading to PA remodeling and hypertension. Our results further indicate that specific pharmacological and genetic RISP, RyR2, FKBP12.6 dissociation, ATM, and Chk2 inhibition may become specific and effective treatment options for PH and other relevant vascular diseases.