Adam Greenstein

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

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 &mgr;m2, 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-&agr; 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.

Effects of Bariatric Surgery on Human Small Artery Function: Evidence for Reduction in Perivascular Adipocyte Inflammation, and the Restoration of Normal Anticontractile Activity Despite Persistent Obesity

Objectives The aim of this study was to investigate the effects of bariatric surgery on small artery function and the mechanisms underlying this. Background In lean healthy humans, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity-associated conditions such as the metabolic syndrome and type II diabetes where there is evidence of adipocyte inflammation and increased oxidative stress. Methods Segments of small subcutaneous artery and perivascular fat were harvested from severely obese individuals before (n = 20) and 6 months after bariatric surgery (n = 15). Small artery contractile function was examined in vitro with wire myography, and perivascular adipose tissue (PVAT) morphology was assessed with immunohistochemistry. Results The anticontractile activity of PVAT was lost in obese patients before surgery when compared with healthy volunteers and was restored 6 months after bariatric surgery. In vitro protocols with superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals before surgery. The improvement in anticontractile function after surgery was accompanied by improvements in insulin sensitivity, serum glycemic indexes, inflammatory cytokines, adipokine profile, and systolic blood pressure together with increased PVAT adiponectin and nitric oxide bioavailability and reduced macrophage infiltration and inflammation. These changes were observed despite the patients remaining severely obese. Conclusions Bariatric surgery and its attendant improvements in weight, blood pressure, inflammation, and metabolism collectively reverse the obesity-induced alteration to PVAT anticontractile function. This reversal is attributable to reductions in local adipose inflammation and oxidative stress with improved adiponectin and nitric oxide bioavailability.

Vascular function in older adults with depressive disorder

BACKGROUND Cerebrovascular disease plays an important role in depressive disorder, especially in older adults. An understanding of vascular function in depression is important etiologically and to develop innovative treatments that may improve prognosis by ameliorating vascular damage. METHODS This study assessed endothelial function, arterial stiffness, and atherosclerosis in a variety of vessel beds in 25 elderly subjects with depressive disorder compared with 21 nondepressed control subjects. Subjects underwent pulse wave velocity, pulse wave analysis, carotid intima media thickness analysis, and magnetic resonance imaging. A subset (16 patients and 15 control subjects) had assessment of biopsied small artery dilatation to acetylcholine to further assess endothelial function. RESULTS The mean sample age was 72.4 years with an average age at onset for depression of 60 years. Mean carotid intima media thickness was significantly higher in depressed subjects (p < .01). Pulse wave velocity was 1.6 m/sec higher in depressed subjects (borderline significance). There was a significant reduction in the dilatation response to acetylcholine in preconstricted small arteries (p = .01). On magnetic resonance imaging, depressed subjects had significantly more dilated Virchow-Robin spaces in the basal ganglia (p = .01). Depressed subjects had greater volume of white matter lesions in all regions, but this did not reach statistical significance. There were no baseline differences in vascular risk. CONCLUSIONS Depression in the elderly is associated with poorer endothelial function and more atherosclerosis. This is associated with a greater white matter hyperintensities lesion load and basal ganglia microangiopathy. The use of vasoprotective drugs to improve endothelial function or retard atherosclerosis as depression-modifying agents should be explored.

Perivascular adipose tissue from human systemic and coronary vessels: The emergence of a new pharmacotherapeutic target

Fat cells or adipocytes are distributed ubiquitously throughout the body and are often regarded purely as energy stores. However, recently it has become clear that these adipocytes are engine rooms producing large numbers of metabolically active substances with both endocrine and paracrine actions. White adipocytes surround almost every blood vessel in the human body and are collectively termed perivascular adipose tissue (PVAT). It is now well recognized that PVAT not only provides mechanical support for any blood vessels it invests, but also secretes vasoactive and metabolically essential cytokines known as adipokines, which regulate vascular function. The emergence of obesity as a major challenge to our healthcare systems has contributed to the growing interest in adipocyte dysfunction with a view to discovering new pharmacotherapeutic agents to help rescue compromised PVAT function. Very few PVAT studies have been carried out on human tissue. This review will discuss these and the hypotheses generated from such research, as well as highlight the most significant and clinically relevant animal studies showing the most pharmacological promise.

Vascular remodeling: Implications for small artery function and target organ damage

At the level of the small artery, essential hypertension is associated with eutrophic inward remodeling. This involves reduction in lumen diameter by an increase in wall thickness. Previously thought to involve either hypertrophy or hyperplasia of the vascular smooth muscle cells in the media, it is now felt to be mediated by a functional property of the wall: myogenic tone. This is the ability of an artery to contract in response to an increase in intraluminal pressure. This autoregulatory function is also vital to ensure stabilisation of distal capillary pressures and so prevent, or limit, organ damage. Indeed in any animal model studied, when myogenic autoregulation is affected, target organ damage ensues. We have also observed, in two studies, that when myogenic autoregulation is damaged in the context of hypertension, eutrophic remodeling is replaced by an outward growth of the arterial wall with preservation of lumen diameter. This is called hypertrophic remodeling and, independently, has been observed by a number of groups in small arteries from patients with type 2 diabetes. We believe that this is a key reason for the unique propensity to hypertensive injury seen in patients with diabetes. We also discuss the significance of integrins, transmembrane proteins with wide ranging functions; from initiation of cell migration to intracellular signalling. Two particular integrins, α5β1 and ανβ3, have been found to be necessary for both normal myogenic autoregulation and eutrophic remodeling and the possibility that damage to these may occur in diabetes is examined.

Cerebrovascular Damage in Late-Life Depression Is Associated With Structural and Functional Abnormalities of Subcutaneous Small Arteries

Late-life depression is increasingly viewed as a vascular illness because of patients exhibiting characteristic white matter brain lesions and in vivo large artery endothelial dysfunction. However, the “vascular depression” hypothesis pertains to the microvasculature, and this circulation has not been studied in this context. Our objective was to examine structure and function of small subcutaneous arteries in patients with late-life depression. Thus, 16 patients aged 71.8±4.0 years with late-life depression were compared with 15 control participants aged 72.1±5.9 years. There were similar cardiovascular profiles between the 2 groups. All of the participants underwent MRI brain scans and subcutaneous gluteal fat biopsy from which small arteries were isolated and studied using pressure myography. Cerebral microvascular damage in depressed patients was confirmed by assessment of basal ganglia Virchow-Robin space scores (depressed patients 3.9±1.7 versus controls: 2.5±1.6; P=0.01). Contractility to norepinephrine was equivalent in both groups, but relaxation of the small arteries to acetylcholine was significantly reduced in depressed patients (84.0±4.0%) compared with control participants (96.0±1.4%; P=0.012). This difference in arterial relaxation was reduced but not entirely eliminated when NO synthase was inhibited. Depressed patients also exhibited hypertrophic wall growth with an increase in medial cross-sectional area (P=0.035, multiple ANOVA and wall thickness; P=0.04, multiple ANOVA). In conclusion, despite similar cardiovascular profiles, depressed patients with cerebral microvascular damage show abnormalities of subcutaneous small artery structure and function.

Myogenic tone and small artery remodelling: insight into diabetic nephropathy

Diabetic nephropathy is the single most frequent cause of end-stage renal disease (ESRD) in the western world, with an estimated cost in excess of

Effects of Obesity on Perivascular Adipose Tissue Vasorelaxant Function: Nitric Oxide, Inflammation and Elevated Systemic Blood Pressure.

15.6 billion per annum in the United States alone [1]. In anticipation of an obesity-related diabetes epidemic, coupled with progressively growing rates of hypertension, these figures are forecast to rise exponentially. As both diabetes and renal disease are increasingly recognized as generalized vasculopathic states, there has been renewed interest in identifying potential vascular mechanisms influencing renal damage. The relationship between diabetes, hypertension and kidney disease is complex, progressive and reciprocal. In type 1 diabetes, the prevalence of microalbuminuria increases from the onset of disease, reaching 50% after 20 years [2], whilst in type 2 diabetes, it is stable at 20–25% [3]. Microalbuminuria is a powerful marker for progression to overt nephropathy [4–6] and renal function continues to decline in 30% of microalbuminuric patients with either type 1 [7] or type 2 diabetes [6]. Whilst in patients with type 1 diabetes, good glycaemic control [8] or relative youth [7] is associated with the remission of microalbuminuria, in patients with type 2 diabetes, institution of antihypertensive therapy is also important [6]. Once nephropathy is established however, ESRD occurs in 75% of individuals within 20 years [1]; at which point the cardiac mortality risk is 20-fold higher than that of the general population [9]. Thus, the stage at which diabetic renal disease is most likely to be arrested and even reversed is at the point at which microalbuminuria is detected by the clinician. The reversibility of microalbuminuria suggests an associated

Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes:

Introduction: Perivascular adipose tissue (PVAT) surrounds most vessels in the human body. Healthy PVAT has a vasorelaxant effect which is not observed in obesity. We assessed the contribution of nitric oxide (NO), inflammation and endothelium to obesity-induced PVAT damage. Methods: Rats were fed a high-fat diet or normal chow. PVAT function was assessed using wire myography. Skeletonised and PVAT-intact mesenteric vessels were prepared with and without endothelium. Vessels were incubated with L-NNA or superoxide dismutase (SOD) and catalase. Gluteal fat biopsies were performed on 10 obese and 10 control individuals, and adipose tissue was assessed using proteomic analysis. Results: In the animals, there were significant correlations between weight and blood pressure (BP; r = 0.5, p = 0.02), weight and PVAT function (r = 0.51, p = 0.02), and PVAT function and BP (r = 0.53, p = 0.01). PVAT-intact vessel segments from healthy animals constricted significantly less than segments from obese animals (p < 0.05). In a healthy state, there was preservation of the PVAT vasorelaxant function after endothelium removal (p < 0.05). In endothelium-denuded vessels, L-NNA attenuated the PVAT vasorelaxant function in control vessels (p < 0.0001). In obesity, incubation with SOD and catalase attenuated PVAT-intact vessel contractility in the presence and absence of endothelium (p < 0.001). In obese humans, SOD [Cu-Zn] (SOD1; fold change -2.4), peroxiredoxin-1 (fold change -2.15) and adiponectin (fold change -2.1) were present in lower abundances than in healthy controls. Conclusions: Incubation with SOD and catalase restores PVAT vasorelaxant function in animal obesity. In the rodent model, obesity-induced PVAT damage is independent of endothelium and is in part due to reduced NO bioavailability within PVAT. Loss of PVAT function correlates with rising BP in our animal obesity model. In keeping with our hypothesis of inflammation-induced damage to PVAT function in obesity, there are lower levels of SOD1, peroxiredoxin-1 and adiponectin in obese human PVAT.

Eutrophic Remodeling of Small Arteries in Type 1 Diabetes Mellitus Is Enabled by Metabolic Control A 10-Year Follow-Up Study

Small-dense LDL (SD-LDL) has been particularly implicated in atherosclerosis. It has previously been reported that in non-diabetic people SD-LDL is preferentially glycated. The distribution of glycated apolipoprotein B (glyc-apoB) in lipoproteins in metabolic syndrome (MS) and in type 2 diabetes has not previously been studied. Plasma apoB and glyc-apoB were determined in different apoB-containing lipoproteins including buoyant and SD-LDL in MS (n=18) and type 2 diabetes (DM) [n=48; 12 statin-untreated (DM−S) and 36 statin-treated (DM+S)]. Plasma glyc-apoB was 5.6 ± 0.9, 3.5 ± 0.5 and 4.0 ± 0.2 mg/dl in DM−S, DM+S and MS, respectively. The glycated proportion of SD-LDL-apoB was greater than buoyant LDL in all groups. SD-LDL contributed most to plasma glyc-apoB in DM−S, because SD-LDL-apoB was higher in DM−S than in MS and DM+S (p < 0.001). Plasma glyc-apoB correlated with SD-LDL-apoB (r=0.74, p < 0.0001 in diabetes and r=0.53, p < 0.001 in MS), but not with HbA1c. SD-LDL is preferentially glycated in type 2 diabetes and MS. Its concentration is a stronger determinant of plasma glycapoB than glycaemia. Statin-induced changes in its level may be important in decreasing apoB glycation in diabetes. These findings may explain the small effect of improving glycaemia relative to statin treatment in reducing atherosclerosis risk in type 2 diabetes and the increased risk in MS even before the onset of type 2 diabetes.