Tianyi Qiu1, Min Li2, Miles A Tanner2, Yan Yang2, James R Sowers1, Ronald J Korthuis1, Michael A Hill3. 1. Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA. 2. Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA. 3. Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA. Electronic address: hillmi@missouri.edu.
Abstract
BACKGROUND: Accumulation of multiple subtypes of immune cells in perivascular adipose tissue (PVAT) has been proposed to cause vascular inflammation and dysfunction in type 2 diabetes (T2DM). This study was designed to investigate specific roles for dendritic cells in PVAT in the development of vascular inflammation and impaired PVAT-mediated vasorelaxation in T2DM. METHODS AND RESULTS: Studies were performed using db/db mice (model of T2DM) and their Db heterozygote (DbHET), lean and normoglycemic controls. Dendritic cell depletion was performed by cross-breeding DbHet with Flt3l-/- (null for ligand for FMS-kinase tyrosine kinase) mice. Using PCR, it was found that the majority of dendritic cells (CD11c+) were located in PVAT rather than the vascular wall. Flow cytometry similarly showed greater dendritic cell accumulation in adipose tissue from db/db mice than DbHET controls. Adipose tissue from db/db mice displayed increased mRNA levels of proinflammatory cytokines TNF-α and IL-6 and decreased mRNA levels of the anti-inflammatory mediator adiponectin, compared to DbHET mice. Depletion of dendritic cells in dbFlt3l-/dbFlt3l- (confirmed by flow cytometry) reduced TNF-α and IL-6 mRNA levels in diabetic adipose tissue without influencing adiponection expression. Moreover, in mesenteric arteries, dendritic cell depletion improved the ability of PVAT to augment acetylcholine-induced vasorelaxation and anti-contractile activity. CONCLUSIONS: In a murine model of T2DM, dendritic cells accumulated predominantly in PVAT, as opposed to the vessel wall, per se. Accumulation of dendritic cells in PVAT was associated with overproduction of pro-inflammatory cytokines, which contributed to an impaired ability of PVAT to augment vasorelaxation and exert anti-contractile activity in T2DM.
BACKGROUND: Accumulation of multiple subtypes of immune cells in perivascular adipose tissue (PVAT) has been proposed to cause vascular inflammation and dysfunction in type 2 diabetes (T2DM). This study was designed to investigate specific roles for dendritic cells in PVAT in the development of vascular inflammation and impaired PVAT-mediated vasorelaxation in T2DM. METHODS AND RESULTS: Studies were performed using db/dbmice (model of T2DM) and their Db heterozygote (DbHET), lean and normoglycemic controls. Dendritic cell depletion was performed by cross-breeding DbHet with Flt3l-/- (null for ligand for FMS-kinase tyrosine kinase) mice. Using PCR, it was found that the majority of dendritic cells (CD11c+) were located in PVAT rather than the vascular wall. Flow cytometry similarly showed greater dendritic cell accumulation in adipose tissue from db/dbmice than DbHET controls. Adipose tissue from db/dbmice displayed increased mRNA levels of proinflammatory cytokines TNF-α and IL-6 and decreased mRNA levels of the anti-inflammatory mediator adiponectin, compared to DbHETmice. Depletion of dendritic cells in dbFlt3l-/dbFlt3l- (confirmed by flow cytometry) reduced TNF-α and IL-6 mRNA levels in diabetic adipose tissue without influencing adiponection expression. Moreover, in mesenteric arteries, dendritic cell depletion improved the ability of PVAT to augment acetylcholine-induced vasorelaxation and anti-contractile activity. CONCLUSIONS: In a murine model of T2DM, dendritic cells accumulated predominantly in PVAT, as opposed to the vessel wall, per se. Accumulation of dendritic cells in PVAT was associated with overproduction of pro-inflammatory cytokines, which contributed to an impaired ability of PVAT to augment vasorelaxation and exert anti-contractile activity in T2DM.
Authors: Claudia Agabiti-Rosei; Carolina De Ciuceis; Claudia Rossini; Enzo Porteri; Luigi F Rodella; Sarah B Withers; Anthony M Heagerty; Gaia Favero; Enrico Agabiti-Rosei; Damiano Rizzoni; Rita Rezzani Journal: J Hypertens Date: 2014-06 Impact factor: 4.844
Authors: H C Probst; K Tschannen; B Odermatt; R Schwendener; R M Zinkernagel; M Van Den Broek Journal: Clin Exp Immunol Date: 2005-09 Impact factor: 4.330
Authors: Sarah B Withers; Laura Simpson; Sharif Fattah; Matthias E Werner; Anthony M Heagerty Journal: Cardiovasc Res Date: 2013-10-04 Impact factor: 10.787
Authors: Rick I Meijer; Wineke Bakker; Caro-Lynn A F Alta; Pieter Sipkema; John S Yudkin; Benoit Viollet; Erik A Richter; Yvo M Smulders; Victor W M van Hinsbergh; Erik H Serné; Etto C Eringa Journal: Diabetes Date: 2012-10-09 Impact factor: 9.461
Authors: Camila Manrique-Acevedo; Jaume Padilla; Huma Naz; Makenzie L Woodford; Thaysa Ghiarone; Annayya R Aroor; Jack L Hulse; Francisco J Cabral-Amador; Vanesa Martinez-Diaz; Chetan P Hans; Adam Whaley-Connell; Luis A Martinez-Lemus; Guido Lastra Journal: Front Physiol Date: 2021-03-29 Impact factor: 4.566