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The current study sought to elucidate the mechanisms linking ceramide accumulation with PP2A activation and determine whether pharmacological inhibition of PP2A in vivo normalizes obesity-associated vascular dysfunction and limits the severity of hypertension. We show in endothelial cells that ceramide associates with the inhibitor 2 of PP2A (I2PP2A) in the cytosol, which disrupts the association of I2PP2A with PP2A leading to its translocation to the plasma membrane. The increased association between PP2A and eNOS at the plasma membrane promotes dissociation of an Akt-Hsp90-eNOS complex that is required for eNOS phosphorylation and activation. A novel small-molecule inhibitor of PP2A attenuated PP2A activation, prevented disruption of the Akt-Hsp90-eNOS complex in the vasculature, preserved arterial function, and maintained normal blood pressure in obese mice. These findings reveal a novel mechanism whereby ceramide initiates PP2A colocalization with eNOS and demonstrate that PP2A activation precipitates vascular dysfunction in diet-induced obesity. Therapeutic strategies targeted to reducing PP2A activation might be beneficial in attenuating vascular complications that exist in the context of type 2 diabetes, obesity, and conditions associated with insulin resistance.<\/jats:p>","DOI":"10.2337\/db15-0244","type":"journal-article","created":{"date-parts":[[2015,8,8]],"date-time":"2015-08-08T02:30:15Z","timestamp":1439001015000},"page":"3914-3926","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":125,"title":["Ceramide-Initiated Protein Phosphatase 2A Activation Contributes to Arterial Dysfunction In Vivo"],"prefix":"10.2337","volume":"64","author":[{"given":"Leena P.","family":"Bharath","sequence":"first","affiliation":[{"name":"College of Health, The University of Utah, Salt Lake City, UT"},{"name":"Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT"},{"name":"Molecular Medicine Program, The University of 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