Published Online
on March 16, 2009

A more recent version of this article appeared on March 31, 2009

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Submitted on September 15, 2008
Accepted on January 26, 2009

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, and 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.

^* To whom correspondence should be addressed. E-mail: tony.heagerty{at}manchester.ac.uk.

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.

Key words: hypoxia • inflammation • obesity • microcirculation • nitric oxide synthase

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