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 111Ϯ2.8 versus 91.1Ϯ3.5 cm in control subjects, PϽ0.001; insulin sensitivity 41Ϯ5.9% versus 121Ϯ18.6% in control subjects, PϽ0.001), the loss of this dilator effect was accompanied by an increase in adipocyte area (1786Ϯ346 versus 673Ϯ60 m 2 , PϽ0.01) and immunohistochemical evidence of inflammation (tumor necrosis factor receptor 1 12.4Ϯ1.1% versus 6.7Ϯ1%, PϽ0.001). 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 Ⅲ inflammation Ⅲ obesity Ⅲ microcirculation Ⅲ nitric oxide synthase M etabolic syndrome is a precursor to type 2 diabetes mellitus and cardiovascular disease, with a prevalence of almost 40% in the adult population. 1 Central obesity is believed to be the main cause of metabolic syndrome, and this is reflected in newer definitions of the condition with large waist circumference as a prerequisite. 2 Although associations of obesity with hypertension, 3 insulin resistance, 4 and cardiovascular disease 5 are well described, the underlying mechanisms are poorly understood. Two areas of research that may provide insight into these are the vasoactive properties of perivascular adipose tissue (PVAT) and the inflammatory changes that occur in fat as obesity develops. Demonstrated in 1991, 6 it is now accepted that healthy PVAT has an anticontractile effect. [7][8][9][10] The mechanism appears to be both endothelium dependent via release of nitric oxide 8,10 and endothelium-independent via generation of hydrogen peroxide. 8 In obesity and metabolic syndrome, there is also a conformational chang...

Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fiftyfour diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy. Diabetes

Following a previous description of nociceptive nerve fibre growth into usually aneural inner parts of painful intervertebral disc (IVD), this study has investigated whether nociceptive nerve ingrowth into painful IVD is stimulated by local production of neurotrophins. Immunohistochemistry and in situ hybridization have been used to investigate expression of the candidate neurotrophin, nerve growth factor (NGF), and its high- and low-affinity receptors trk-A and p75, respectively, in painful IVD excised for the management of low back pain. IVD from patients with back pain were of two types: those that when examined by discography reproduced the patient symptoms (pain level IVD) and those that did not (non-pain level IVD). Microvascular blood vessels accompanied nerve fibres growing into pain level IVD and these expressed NGF. The adjacent nerves expressed the high-affinity NGF receptor trk-A. These vessels entered the normally avascular IVD through the discal end plates. NGF expression was not identified in non-pain level or control IVD. Some non-pain level IVD had vessels within them, which entered through the annulus fibrosus. These did not express NGF nor did nerves accompany them. These findings show that nociceptive nerve ingrowth into painful IVD is causally linked with NGF production by blood vessels growing into the IVD, from adjacent vertebral bodies.