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(Circulation. 2009;119:1661-1670.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Local Inflammation and Hypoxia Abolish the Protective Anticontractile Properties of Perivascular Fat in Obese Patients

Adam S. Greenstein, MBChB, MRCP; Kaivan Khavandi, MSc, MBChB; Sarah B. Withers, BSc, PhD; Kazuhiko Sonoyama, MD; Olivia Clancy, MSc, MBChB; Maria Jeziorska, MD, PhD; Ian Laing, PhD; Allen P. Yates, PhD; Philip W. Pemberton, MSc; Rayaz A. Malik, PhD, FRCP; Anthony M. Heagerty, MN, FRCP, FMedSci

From the Cardiovascular Research Group (A.S.G., K.K., S.B.W., K.S., O.C., R.A.M., A.M.H.) and the Department of Regenerative Medicine, Laboratory and Clinical Sciences (M.J.), University of Manchester, Manchester, United Kingdom; and the Wellcome Trust Clinical Research Facility (A.S.G, A.M.H.) and Department of Clinical Biochemistry, Manchester Royal Infirmary (I.L., A.P.Y., P.W.P.), Manchester, United Kingdom.

Correspondence to Professor Anthony Heagerty, Cardiovascular Research Group, Core Technology Facility, 46 Grafton St, Manchester M13 9NT, United Kingdom. E-mail tony.heagerty{at}manchester.ac.uk

Received September 15, 2008; accepted January 26, 2009.

Background— Inflammation in adipose tissue has been implicated in vascular dysfunction, but the local mechanisms by which this occurs are unknown.

Methods and Results— Small arteries with and without perivascular adipose tissue were taken from subcutaneous gluteal fat biopsy samples and studied with wire myography and immunohistochemistry. We established that healthy adipose tissue around human small arteries secretes factors that influence vasodilation by increasing nitric oxide bioavailability. However, in perivascular fat from obese subjects with metabolic syndrome (waist circumference 111±2.8 versus 91.1±3.5 cm in control subjects, P<0.001; insulin sensitivity 41±5.9% versus 121±18.6% in control subjects, P<0.001), the loss of this dilator effect was accompanied by an increase in adipocyte area (1786±346 versus 673±60 µm², P<0.01) and immunohistochemical evidence of inflammation (tumor necrosis factor receptor 1 12.4±1.1% versus 6.7±1%, P<0.001). Application of the cytokines tumor necrosis factor receptor- and interleukin-6 to perivascular fat around healthy blood vessels reduced dilator activity, resulting in the obese phenotype. These effects could be reversed with free radical scavengers or cytokine antagonists. Similarly, induction of hypoxia stimulated inflammation and resulted in loss of anticontractile capacity, which could be rescued by catalase and superoxide dismutase or cytokine antagonists. Incubation with a soluble fragment of adiponectin type 1 receptor or inhibition of nitric oxide synthase blocked the vasodilator effect of healthy perivascular adipose tissue.

Conclusions— We conclude that adipocytes secrete adiponectin and provide the first functional evidence that it is a physiological modulator of local vascular tone by increasing nitric oxide bioavailability. This capacity is lost in obesity by the development of adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress.

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