title: 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.
  
  
  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.
authors.affiliation: Research Unit, Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Indranil
authors.initials: I
authors.lastname: Bhattacharya
authors.forename: Katja
authors.initials: K
authors.lastname: Drägert
authors.forename: Verena
authors.initials: V
authors.lastname: Albert
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Contassot
authors.forename: Marlen
authors.initials: M
authors.lastname: Damjanovic
authors.forename: Asami
authors.initials: A
authors.lastname: Hagiwara
authors.forename: Lukas
authors.initials: L
authors.lastname: Zimmerli
authors.forename: Rok
authors.initials: R
authors.lastname: Humar
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.forename: Edouard J
authors.initials: EJ
authors.lastname: Battegay
authors.forename: Elvira
authors.initials: E
authors.lastname: Haas
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D017077:Culture Media, Conditioned; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C577686:interleukin-6, mouse; C525637:rictor protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: adipose tissue; inflammation; mammalian target of rapamycin complex 2; nitric oxide synthase type II; perivascular adipose tissue; thoracic aorta