Rictor in Perivascular Adipose Tissue Controls Vascular Function by Regulating Inflammatory Molecule Expression

Abstract

Objective— Perivascular adipose tissue (PVAT) wraps blood vessels and modulates vasoreactivity by secretion of vasoactive molecules. Mammalian target of rapamycin complex 2 (mTORC2) has been shown to control inflammation and is expressed in adipose tissue. In this study, we investigated whether adipose-specific deletion of rictor and thereby inactivation of mTORC2 in PVAT may modulate vascular function by increasing inflammation in PVAT. Approach and Results— Rictor, an essential mTORC2 component, was deleted specifically in mouse adipose tissue (rictor ad−/− ). Phosphorylation of mTORC2 downstream target Akt at Serine 473 was reduced in PVAT from rictor ad−/− mice but unaffected in aortic tissue. Ex vivo functional analysis of thoracic aortae revealed increased contractions and impaired dilation in rings with PVAT from rictor ad−/− mice. Adipose rictor knockout increased gene expression and protein release of interleukin-6, macrophage inflammatory protein-1α, and tumor necrosis factor-α in PVAT as shown by quantitative real-time polymerase chain reaction and Bioplex analysis for the cytokines in the conditioned media, respectively. Moreover, gene and protein expression of inducible nitric oxide synthase was upregulated without affecting macrophage infiltration in PVAT from rictor ad−/− mice. Inhibition of inducible nitric oxide synthase normalized vascular reactivity in aortic rings from rictor ad−/− mice with no effect in rictor fl/fl mice. Interestingly, in perivascular and epididymal adipose depots, high-fat diet feeding induced downregulation of rictor gene expression. Conclusions— Here, we identify mTORC2 as a critical regulator of PVAT-directed protection of normal vascular tone. Modulation of mTORC2 activity in adipose tissue may be a potential therapeutic approach for inflammation-related vascular damage.

Adventitia and Perivascular Cells

“…23 Moreover, a high fat diet alone was sufficient to induce downregulation of rictor gene expression in PVAT and epididymal adipose depots. 23 These studies suggest that controlling mTORC2 activity in perivascular adipose tissues may offer a therapeutic avenue for inflammation-driven cardiovascular damage frequently observed in obesity.…”

“…Mammalian target of rapamycin complex 2 (mTORC2) is reported to control inflammation and is expressed in PVAT. 23 When rictor, an essential mTORC2 component, was deleted in mouse adipose tissue, gene expression and protein release of IL6, MIP-1α, and TNFα, were increased and dilations of aortic rings were impaired. 23 Moreover, a high fat diet alone was sufficient to induce downregulation of rictor gene expression in PVAT and epididymal adipose depots.…”

“…23 When rictor, an essential mTORC2 component, was deleted in mouse adipose tissue, gene expression and protein release of IL6, MIP-1α, and TNFα, were increased and dilations of aortic rings were impaired. 23 Moreover, a high fat diet alone was sufficient to induce downregulation of rictor gene expression in PVAT and epididymal adipose depots. 23 These studies suggest that controlling mTORC2 activity in perivascular adipose tissues may offer a therapeutic avenue for inflammation-driven cardiovascular damage frequently observed in obesity.…”

Vascular Function

“…Mammalian target of rapamycin complex 2 has been shown to control inflammation and is expressed in adipose tissue. Bhattacharya et al 32 identified mammalian target of rapamycin complex 2 as a critical regulator of perivascular adipose tissue-directed protection of normal vascular tone. They concluded that modulation of mammalian target of rapamycin complex 2 activity in adipose tissue is a potential therapeutic approach for inflammationrelated vascular damage.…”

“…They concluded that modulation of mammalian target of rapamycin complex 2 activity in adipose tissue is a potential therapeutic approach for inflammationrelated vascular damage. 32 …”