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Vascular events can trigger a pathological phenotypic switch in vascular smooth muscle cells (VSMCs), decreasing and disrupting the plasticity and diversity of vascular networks. The development of novel therapeutic approaches is necessary to prevent these changes. We aimed to investigate the effects and associated mechanisms of low-intensity pulsed ultrasound (LIPUS) irradiation on the angiotensin II (AngII)-induced phenotypic switch in VSMCs. In vivo , AngII was infused subcutaneously for 4 weeks to stimulate vascular remodeling in mice, and LIPUS irradiation was applied for 20 min every 2 days for 4 weeks. In vitro , cultured rat aortic VSMCs (RAVSMCs) were pretreated once with LIPUS irradiation for 20 min before 48-h AngII stimulation. Our results showed that LIPUS irradiation prevents AngII-induced vascular remodeling of the whole wall artery without discriminating between adventitia and media in vivo and RAVSMC phenotypic switching in vitro. LIPUS irradiation downregulated miR-17-5p expression and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. The PPAR-γ activator rosiglitazone could mimic the favorable effects of LIPUS irradiation on AngII-treated RAVSMCs. In contrast, GW9662 could impede the LIPUS-mediated downregulation of RAVSMC proliferation and inflammation under AngII stimulation conditions in vivo and in vitro. Also, the miR-17-5p agomir has the same effects as GW9662 in vitro. Besides, the inhibitory effects of GW9662 against the anti-remodeling effects of LIPUS irradiation in AngII-induced RAVSMCs could be blocked by pretreatment with the miR-17-5p antagomir. Overall, LIPUS irradiation prevents AngII-induced RAVSMCs phenotypic switching through hampering miR-17-5p and enhancing PPAR-γ, suggesting a new approach for the treatment of vascular disorders. [Display omitted] • LIPUS irradiation ameliorates AngII-induced vascular remodeling in vivo. • LIPUS irradiation ameliorates AngII-induced RASMCs phenotypic switch in vitro. • LIPUS irradiation exerts its vascular protective effects via hampering miR-17-5p. • LIPUS irradiation exerts its vascular protective effects via enhancing PPAR-γ. • We provided a novel and safe approach for the treatment of vascular disorders. [ABSTRACT FROM AUTHOR]