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AIMS Adventitial remodeling presenting with the phenotypic switch of adventitial fibroblasts (AFs) to myofibroblasts (MFs) is reportedly involved in the evolution of several vascular diseases, including hypertension. In our previous study, we reported that heat shock protein 90 (HSP90) inhibition by 17-dime-thylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) markedly attenuates angiotensin II (AngII)-induced abdominal aortic aneurysm formation by simultaneously inhibiting several key signaling and transcriptional pathways in vascular smooth muscle cells (VSMCs); however, little is known about its role on AFs. Given that the AF phenotypic switch is likely to be associated with mitochondrial function and calcineurin, a client protein of HSP90 that mediates mitochondrial fission and function, the aim of this study was to investigate whether mitochondrial fission contributes to phenotypic switch of AF, and if it does, we further aimed to determine whether HSP90 inhibition attenuates mitochondrial fission and subsequently suppresses AF transformation and adventitial remodeling in AngII-induced hypertensive mice. METHODS AND RESULTS In primary mouse AFs, we found that calcineurin-dependent dephosphorylation of Drp1 induced mitochondrial fission and regulated mitochondrial ROS production, which stimulated AF proliferation, migration, and phenotypic switching in AngII-treated AFs. Moreover, AngII was found to increase the binding of HSP90 and calcineurin in AFs, while HSP90 inhibition significantly reversed AngII-induced mitochondrial fission and AF phenotypic switching by modulating the calcineurin-dependent dephosphorylation of Drp1. Consistent with the effects in AFs, in an animal model of AngII-induced adventitial remodeling, 17-DMAG markedly reduced mitochondrial fission, AF differentiation, vessel wall thickening, and fibrosis in the aortic adventitia, which were mediated by calcineurin/Drp1 signaling pathways. CONCLUSIONS Our study suggests that calcineurin/Drp1-dependent mitochondrial fission may be essential for understanding adventitial remodeling in hypertension and that HSP90 inhibition may serve as a novel approach for the treatment of adventitial remodeling-related diseases.