BACKGROUND AND AIM: Our previous research indicates that sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) dysfunction facilitates the phenotypic transformation of aortic smooth muscle cells (ASMCs) and intensifies aortic aneurysm through the regulation of calcium-dependent pathways and endoplasmic reticulum stress. Our hypothesis is that additional mechanisms are involved in aortic aneurysm and atherosclerosis induced by SERCA2 dysfunction from the perspective of ASMC phenotypic transformation. METHODS & RESULTS: In SERCA2 dysfunctional mice and their control littermates, ASMCs were isolated to analyze protein expression and cell functions, and angiotensin II was infused into these mice that were backcrossed into LDL receptor deficient background to induce aortic aneurysm and atherosclerosis. In ASMCs from SERCA2 dysfunctional mice, the cell cycle was accelerated, and proliferation and migration were enhanced, which could be reversed by SERCA agonist CDN1163 or calcium chelator BAPTA-AM. In ASMCs, SERCA2 dysfunction increased reactive oxygen species (ROS) production, activating extracellular signal-regulated kinases 1 and 2 (ERK1/2) and angiotensin II/angiotensin II type 1 receptor (AT1R) pathways. Both ERK1/2 and angiotensin II/AT1R activations are implicated in SERCA2 dysfunction-induced ASMC phenotypic transformation and ROS production. The redox modulator Tempol suppressed ERK1/2 and angiotensin II/AT1R pathways, inhibiting ASMC phenotypic transformation and alleviating angiotensin II-induced aortic aneurysm and atherosclerosis. CONCLUSION: SERCA2 dysfunction accelerates aortic aneurysm and atherosclerosis by inducing oxidative stress in ASMCs, with activations of ERK1/2 and angiotensin II/AT1R involved in ASMC phenotypic transformation. Inhibition of oxidative stress in ASMCs is beneficial in alleviating angiotensin II-induced aortic aneurysm and atherosclerosis caused by SERCA2 dysfunction.