Phosphatase and tensin homolog (PTEN) drives perivascular adipose tissue (PVAT) dysfunction in rats fed a high-sugar diet

AIMS: Perivascular adipose tissue (PVAT) dysfunction is a hallmark of obesity-associated vascular disease; however, the molecular mechanisms involved remain incompletely understood. We investigated whether phosphatase and tensin homolog (PTEN) contributes to PVAT dysfunction in male and female rats fed a high-sugar (HS) diet. MATERIALS AND METHODS: A total of 24 Wistar rats (12 males and 12 females) were fed a control (CT) or HS diet for 14 weeks. Vascular reactivity was assessed in aortic rings with or without PVAT. PTEN expression, Akt and eNOS phosphorylation, and nitric oxide (NO) bioavailability were evaluated in PVAT. The functional role of PTEN-Akt signaling was investigated using a PTEN inhibitor and an Akt activator. KEY FINDINGS: The HS diet induced obesity in both sexes. However, PVAT dysfunction occurred exclusively in males, as evidenced by loss of the anticontractile effect of PVAT and impaired endothelium-dependent relaxation. These alterations were accompanied by decreased NO bioavailability, increased PTEN expression, and reduced levels of phosphorylated Akt and eNOS in PVAT. In contrast, female rats maintained normal PVAT function and NO signaling despite developing obesity. Pharmacological inhibition of PTEN or activation of Akt restored the anticontractile properties of PVAT and improved endothelial relaxation in HS-fed males. Furthermore, PTEN inhibition normalized NO production in PVAT. SIGNIFICANCE: PTEN is a mediator of obesity-induced PVAT dysfunction in male rats through suppression of the Akt/eNOS/NO signaling pathway. These findings identify PTEN as potential therapeutic target for obesity-associated vascular dysfunction and highlight important sex-dependent differences in PVAT biology.