ABSTRACT Background and Purpose The pulmonary vascular remodeling (PVR), the pathological basis of pulmonary hypertension (PH), entails pulmonary artery smooth muscle cells (PASMCs) phenotypic switching, but appreciation of the underlying mechanisms is incomplete. Exosomes, a novel transfer machinery enabling delivery of its cargos to recipient cells, have been recently implicated in PH. The two critical questions of whether plasma-derived exosomes drive PASMCs phenotypic switching and what cargo the exosomes transport, however, remain unclear. Experimental Approach PH is induced by exposure of rats to chronic hypoxia (10% O2, 3 weeks). Exosomes were isolated and purified from rat plasma by ultracentrifugation. Exosomal LOX-1 was assessed by transmission electron microscopy and Western blotting. PASMCs phenotypic switching was determined by Western blotting, immunofluorescence staining and flow cytometry. Key Results We characterized lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) as a novel cargo of plasma-derived exosomes in PH. With LOX-1 knockout (Olr1-/-) rats-derived exosomes, we demonstrated that exosomal LOX-1 could be transferred into PASMCs and thus elicited cell phenotypic switching. Of importance, Olr1-/- rats exhibited no cell phenotypic switching and developed less severe PH, but administration of wild type rather than Olr1-/- exosomes to Olr1-/- rats recapitulated the phenotype of PH with robust PASMCs phenotypic switching. We also revealed that exosomal LOX-1 triggered PASMCs phenotypic switching, PVR and ultimately PH via ERK1/2-KLF4 signaling axis. Conclusion and Implications This study has generated proof that plasma-derived exosomes confer PH by delivering LOX-1 into PASMCs. Hence, exosomal LOX-1 represents a novel exploitable target for PH prevention and treatment.