Obese Perivascular Adipose Tissue Research Articles

MiRNA-22 is involved in the aortic reactivity in physiological conditions and mediates obesity-induced perivascular adipose tissue dysfunction

AimsBlood vessels are surrounded by perivascular adipose tissue (PVAT), which plays an important role in vascular tonus regulation due to its anticontractile effect; however, this effect is impaired in obesity. We previously demonstrated that miRNA-22 is involved in obesity-related metabolic disorders. However, the impact of miRNA-22 on vascular reactivity and PVAT function is unknown. AimTo investigate the role of miRNA-22 on vascular reactivity and its impact on obesity-induced PVAT dysfunction. Main methodsWild-type and miRNA-22 knockout (KO) mice were fed a control or a high-fat (HF) diet. To characterize the vascular response, concentration-responses curves to noradrenaline were performed in PVAT- or PVAT+ thoracic aortic rings in absence and presence of L-NAME. Expression of adipogenic and thermogenic markers and NOS isoforms were evaluated by western blotting or qPCR. Key findingsHF diet and miRNA-22 deletion reduced noradrenaline-induced contraction in PVAT- aortic rings. Additionally, miRNA-22 deletion increased noradrenaline-induced contraction in PVAT+ aortic rings without affecting its sensitivity; however, this effect was not observed in miRNA-22 KO mice fed a HF diet. Interestingly, miRNA-22 deletion reduced the contraction of aortic rings to noradrenaline via a NOS-dependent mechanism. Moreover, HF diet abolished the NOS-mediated anticontractile effect of PVAT, which was attenuated by miRNA-22 deletion. Mechanistically, we found that PVAT from miRNA-22 KO mice fed a HF diet presented increased protein expression of nNOS. SignificanceThese results suggest that miRNA-22 is important for aorta reactivity under physiological circumstances and its deletion attenuates the loss of the NOS-mediated anticontractile effect of PVAT in obesity.

Melatonin reverses the loss of the anticontractile effect of perivascular adipose tissue in obese rats.

Perivascular adipose tissue (PVAT) undergoes functional changes in obesity. Increased oxidative stress is a central mechanism whereby obesity induces loss of the anticontractile effect of PVAT. Melatonin is an antioxidant that displays vasoprotective action in cardiovascular disease. Here, we sought to investigate whether melatonin would restore the anticontractile effect of periaortic PVAT in obesity. Male Wistar Hannover rats were treated for 10weeks with a high-calorie diet. Melatonin (5mg/kg/d, p.o., gavage) was administered for 2weeks. Functional findings showed that obesity-induced loss of the anticontractile effect of PVAT and treatment with melatonin reversed this response. Tiron [a scavenger of superoxide anion (O2 - )] restored the anticontractile effect of PVAT in aortas from obese rats, suggesting a role for reactive oxygen species (ROS) in such response. Decreased superoxide dismutase (SOD) activity and augmented levels of ROS were detected in periaortic PVAT from obese rats. These responses were accompanied by decreased levels of nitric oxide (NO) in PVAT. Treatment with melatonin restored SOD activity, decreased ROS levels, and increased NO bioavailability in PVAT from obese rats. Here, we first reported the beneficial effects of melatonin in periaortic PVAT in obesity. Melatonin reversed the adverse effects of obesity in PVAT that included overproduction of ROS, reduced SOD activity, and decreased bioavailability of NO. Therefore, PVAT may constitute an important target for the treatment of obesity-induced vascular dysfunction and melatonin emerges as a potential tool in the management of the vascular complications induced by obesity.

Abstract P099: Loss Of The Brown-Like Phenotype Of Aortic PVAT Is Associated With Mitochondrial Dysfunction In Obesity-Induced Endothelial Dysfunction In Female Rats

Endothelial dysfunction is a major complication of obesity and is an early contributor to hypertension. Perivascular adipose tissue (PVAT) surrounds most blood vessels and has different phenotypic properties based on its anatomical location. Thoracic aortic PVAT from humans and rodents is a brown-like adipose tissue and plays a vasculo-protective role under physiological conditions. In obesity, aortic PVAT expands, switches from a brown-like to a white-like phenotype and contributes to endothelial dysfunction. We hypothesized that loss of the brown-like phenotype of aortic PVAT in obesity is associated with mitochondrial dysfunction, resulting in PVAT and endothelial dysfunction. Eight-week-old female Wistar rats were randomized into two experimental groups: the Lean group (n=8) received a chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) and the Obese group (n=8) received a western diet (21% fat, 50% carbohydrate [34% sucrose], 20% protein), for 20 weeks. Increased body weight (340.57 vs. 265.37g leans, p<0.05) was confirmed in the obese group. At the experimental endpoint, thoracic aortas with intact (+PVAT) or removed PVAT (-PVAT) were obtained for analysis. Endothelial function was assessed in aortic rings +PVAT or -PVAT by performing concentration-response to acetylcholine using wire myography. The aortic ring (-PVAT) from the obese group exhibited impaired endothelium-dependent vasodilation (p<0.01). This effect was heightened in aortic rings (+PVAT) (p<0.05), showing a negative effect of PVAT on endothelial function during obesity. Mitochondrial dysfunction in PVAT from the obese group was characterized by decreased mitochondrial density (30% reduction, p<0.05), detected by quantification of Mitotracker fluorescence, and increased reactive oxygen species levels (4.34-fold increase, p<0.01), as evidenced by DHE staining. These effects were accompanied by decreased uncoupling protein-1 expression in the obese group (55% reduction, p<0.01). Moreover, Oil Red O staining showed larger lipid droplets in aortic PVAT from the obese group. Our results support that obesity-induced endothelial dysfunction is associated with a loss of the brown-like phenotype and mitochondrial dysfunction in PVAT.

C-reactive protein derived from perivascular adipose tissue accelerates injury-induced neointimal hyperplasia

AimInflammation within the perivascular adipose tissue (PVAT) in obesity plays an important role in cardiovascular disorders. C-reactive protein (CRP) level in obesity patients is significantly increased and associated with the occurrence and progression of cardiovascular disease. We tested the hypothesis CRP derived from PVAT in obesity contributes to vascular remodeling after injury.MethodsA high-fat diet (HFD) significantly increased CRP expression in PVAT. We transplanted thoracic aortic PVAT from wild-type (WT) or transgenic CRP-expressing (CRPTG) mice to the injured femoral artery in WT mice.ResultsAt 4 weeks after femoral artery injury, the neointimal/media ratio was increased significantly in WT mice that received PVAT from CRPTG mice compared with that in WT mice that received WT PVAT. Transplanted CRPTG PVAT also significantly accelerated adventitial macrophage infiltration and vasa vasorum proliferation. It was revealed greater macrophage infiltration in CRPTG adipose tissue than in WT adipose tissue and CRP significantly increased the adhesion rate of monocytes through receptor Fcγ RI. Proteome profiling showed CRP over-expression promoted the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) in adipose tissue, transwell assay showed CRP increased monocyte migration indirectly via the induction of CXCL7 expression in adipocytes.ConclusionCRP derived from PVAT was significantly increased in HFD mice and promoted neointimal hyperplasia after vascular injury.

Perivascular adipose tissue-derived extracellular vesicle miR-221-3p mediates vascular remodeling.

Adipose tissue-secreted extracellular vesicles (EVs) containing microRNAs (miRNAs) convey intercellular message signaling. The biogenesis of EV-miRNAs from perivascular adipose tissue (PVAT) and their roles in intercellular communication in response to obesity-associated inflammation have not yet been fully explored. By feeding mice a high-fat diet for 16 wk, we established obesity-associated, chronic low-grade inflammation in PVAT, characterized as hypertrophy of perivascular adipocytes, decreased adipogenesis, and proinflammatory macrophage infiltration. We show that PVAT-derived EVs and their encapsulated miRNAs can be taken up into vascular smooth muscle cells (VSMCs) in vivo and in vitro. miR-221-3p is one of the highly enriched miRNAs in obese PVAT and PVAT-derived EVs. Transfer and direct overexpression of miR-221-3p dramatically enhances VSMC proliferation and migration. Peroxisome proliferator-activated receptor γ coactivator 1α is identified as a miR-221-3p target in VSMC phenotypic modulation. Obese mice secrete abundant miRNA-containing EVs, evoking inflammatory responses in PVAT and vascular phenotypic switching in abdominal aorta of lean mice. Local delivery of miR-221-3p mimic in femoral artery causes vascular dysfunction by suppressing the contractile genes in the arterial wall. Our findings provide an EV-miR-221-3p-mediated mechanism by which PVAT triggers an early-stage vascular remodeling in the context of obesity-associated inflammation.-Li, X., Ballantyne, L. L., Yu, Y., Funk, C. D. Perivascular adipose tissue-derived extracellular vesicle miR-221-3p mediates vascular remodeling.

OP.8C.02] NORADRENERGIC RECEPTOR FUNCTION IN HEALTHY AND OBESE PERIVASCULAR ADIPOSE TISSUE

Objective: Healthy perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating blood pressure, and evidence suggests that sympathetic nervous stimulation of PVAT triggers the release of anti-contractile factors via activation of beta3-adrenoceptors. In obesity there is sympathetic over-activity, which may result in a loss of PVAT function and subsequent hypertension. Therefore we examined beta3-adrenoceptor function in obesity. Design and method: Electrical field stimulation (EFS) profiles of healthy and obese mouse mesenteric arteries (<200um, +/−PVAT) were characterised using wire myography (0.1–30 Hz, 20 V, 0.2ms pulse duration, 4 s train duration). To demonstrate the release of an anti-contractile factor in health, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT denuded vessel. Beta3-adrenoceptor function was investigated using the agonist CL-316,243 (10uM) and antagonist SR59203A (100 nM). The role of the vasodilator nitric oxide (NO) was studied using nitric oxide synthase (NOS) inhibitor L-NMMA (100uM), and NOS activator histamine (100uM). Results: During EFS healthy PVAT elicited an anti-contractile effect; which was lost in obesity. Solution transfer from stimulated healthy exogenous PVAT to a –PVAT vessel significantly reduced contraction, confirming that stimulated PVAT releases a transferable anti-contractile factor. Solution transfer from obese PVAT had no effect on contraction. Inhibition of beta3-adrenoceptors in healthy PVAT using SR59230A significantly reduced the anti-contractile effect, whereas activation of beta3-adrenoceptors in obese PVAT using CL-316,243 did not restore function. Using immunohistochemistry, expression of beta3-adrenoceptors is reduced in obesity. In healthy PVAT, inhibition of NOS using L-NMMA abolished the anti-contractile effect. In obese PVAT, activation of NOS using histamine was able to restore the anti-contractile function. Conclusions: These results demonstrate that in health PVAT releases an anti-contractile factor via activation of beta3-adrenoreceptors, which downstream triggers the release of NO. In obesity, the anti-contractile effect is lost and cannot be restored by beta3-activation, but is restored by activation of NOS. This reveals that in obesity beta3-adrenoreceptors are downregulated, leading to a loss of anti-contractile function, which may contribute to the development of hypertension. Targeting the NOS pathway may restore anti-contractile function, and treat the vascular complications of obesity.

YIA 03-09 NORADRENERGIC RECEPTOR FUNCTION IN HEALTHY AND OBESE PERIVASCULAR ADIPOSE TISSUE

Objective: Perivascular adipose tissue (PVAT) exerts an anti-contractile effect vital to regulating blood pressure. Evidence suggests that the sympathetic nervous stimulation of PVAT triggers the release of anti-contractile factors via activation of β3-adrenoceptors. Therefore it was decided to examine β3-adrenoceptor function in obesity. Design and Method: Electrical field stimulation (EFS) of healthy and obese mouse mesenteric arteries (<200 μm, +/-PVAT) were characterised using wire myography (0.1–30 Hz, 20V, 0.2ms pulse duration, 4s train duration). To demonstrate the release of an anti-contractile factor in health, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT denuded vessel. β3-adrenoceptor function was investigated using the agonist CL-316,243 (10 μM) and antagonist SR59203A (100nM). The role of the vasodilator nitric oxide (NO) was studied using nitric oxide synthase (NOS) inhibitor L-NMMA (100 μM), and NOS activator histamine (100 μM). Results: Healthy PVAT elicits an anti-contractile effect which was lost in obesity. Inhibition of β3-adrenoceptors significantly reduced the anti-contractile effect, whereas activation of β3-adrenoceptors in obese PVAT using CL-316,243 did not restore function. Solution transfer from stimulated healthy exogenous PVAT to a –PVAT vessel significantly reduced contraction, confirming the release of a transferable factor. The release of this factor could be inhibited using SR59230A. Solution transfer from obese PVAT had no effect on contraction, and again could not be restored using CL-316,243. In healthy PVAT, inhibition of NOS using L-NMMA abolished the anti-contractile effect. In obese PVAT, activation of NOS using histamine was able to restore the anti-contractile function. Conclusions: These results demonstrate that healthy PVAT releases an anti-contractile factor via activation of β3-adrenoreceptors, which downstream triggers the release of NO. In obesity, the anti-contractile effect is lost and cannot be restored by β3-activation, but is restored by activation of NOS. This suggests that in obesity β3-adrenoreceptors must be downregulated or desensitised, leading to a loss of anti-contractile function.

Adventitia and perivascular cells.

The past few years have seen significant advances in our understanding of the multiple and dynamic roles of the adventitia and its companion perivascular tissues for vessel wall homeostasis and disease. It is now becoming clear that signals originating from within the adventitia and from perivascular cells play essential roles in regulation of vascular development, physiology, artery wall remodeling, immune surveillance, and vascular disease.1–4 The adventitia is in contact with and completely surrounds the media and is the interface between the vessel wall and its neighboring tissues. It contains many different interacting cell types including fibroblasts, microvascular endothelium, nerves, resident macrophages, T cells, B cells, mast cells, and dendritic cells.5–9 The adventitia is also home to resident vascular progenitor cells whose formation and maintenance depend, in part, on sonic hedgehog signaling.1,10–12 Perivascular cells are in close contact with the adventitia, particularly for the aorta and coronary arteries. Perivascular tissue includes adipocytes, lymphatic vessels, perivascular nerves, and stromal cells exhibiting mesenchymal stem cell–like properties.3,13 The adventitia and periadventitial cells function in concert. They are linked by microvessels, nerves, and migratory cells to regulate vascular physiology, homeostasis, structural remodeling, and exert major influences on the progression or regression of vascular disease. Crosstalk between intima, media, and adventitia further links the adventitia-periadventitial unit to the rest of the vessel wall. Much of the work advancing our concepts of the adventitia and periadventitial tissues has been published in ATVB , and some of those key studies are discussed in this highlights article. In the following summary, areas that have attracted the most interest over the past 2 years in ATVB are reviewed including the multiple roles of perivascular adipose tissue (PVAT) on control of vascular physiology and remodeling, adventitial progenitor …

Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and restoration of normal anticontractile activity despite persistent obesity

BackgroundIn lean healthy human beings, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity where there is evidence of adipocyte inflammation and increased oxidative stress. The aim of this study was to investigate the effects of bariatric surgery on small artery function and the underlying mechanisms. MethodsSmall arteries were isolated from subcutaneous adipose tissue samples obtained by gluteal biopsies from morbidly obese patients (n=15). Vessels were prepared as segments with and without intact PVAT. Response of vessel segments to cumulative doses of norepinephrine was recorded with wire myography. Biopsy samples were re-taken 6 months after bariatric surgery and effect of PVAT on vessel contractility was re-assessed. Vessel segments with intact PVAT were also incubated with blocking peptide for adiponectin receptor 1 (1·6 × 10−4 mol/L, n=5). PVAT adiponectin levels were assessed by proteomic analysis of samples from obese (n=13) and control (n=10) individuals. Inflammatory profile of PVAT was assessed by staining for macrophages and tumour necrosis factor α. FindingsObese patients had a mean body-mass index of 52 kg/m2; 6 months following surgery and significant weight loss (p<0·05), patients remained clinically obese. There were significant improvements in serum biomarkers including adiponectin (p=0·009), as well as inflammatory markers and measures of insulin sensitivity. Proteomic analysis of PVAT showed that adiponectin levels were low in the obese group compared with controls (fold change 2·1, p<0·05). Presence of PVAT made no difference in contractility of vessels to noradrenaline in samples from obese patients (p=0·81). However, post weight loss, PVAT had a significant anticontractile effect (p<0·001) which was lost after incubation with adiponectin receptor 1 blocking peptide. There was a significant reduction in inflammation post surgery. InterpretationDamage to the anticontractile property of PVAT in obesity is in part due to a reduction in adiponectin levels within the PVAT and is rescued by weight loss following bariatric surgery. FundingBritish Heart Foundation.

Interplay between adipose tissue and blood vessels in obesity and vascular dysfunction

There is a close anatomical and functional relationship between adipose tissue and blood vessels. The crosstalk between these two organs is vital to both metabolic and vascular homeostasis. On the one hand, adipose tissue is highly vascularized, and maintenance of ample supply of blood flow is essential for both expansion and metabolic functions of adipose tissue. Vascular endothelium also secretes many factors to regulate adipogenesis and adipose tissue remodeling. On the other hand, almost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which regulates vascular function by producing a large number of "vasocrine" molecules. Under the normal conditions, PVAT exerts its anti-contractile effects by release of vasorelaxants (such as adipocyte-derived relaxation factors and adiponectin) that promote both endothelium-dependent and -independent relaxations of blood vessels. However, PVAT in obesity becomes highly inflamed and induces vascular dysfunction by augmented secretion of vasoconstriction factors (such as the major components of renin-angiotensinogen-aldosterone system and superoxide) and pro-inflammatory adipokines (such as TNF-α and adipocyte fatty acid binding protein), the latter of which are important contributors to endothelial activation, vascular inflammation and neointimal formation. Furthermore, several adipocyte-derived adipokines impair vascular function indirectly, by acting in the brain to activate sympathetic nerve system (such as leptin) or by exerting their actions in major metabolic organs to induce vascular insulin resistance, which in turn aggravates endothelial dysfunction. Aberrant secretion of adipokines and other vasoactive factors in adipose tissue is a major contributor to the onset and progression of obesity-related metabolic and vascular complications.

Epicardial perivascular adipose tissue as a therapeutic target in obesity‐related coronary artery disease

Adipose tissue is an active endocrine and paracrine organ that may influence the development of atherosclerosis and vascular disease. In the setting of obesity, adipose tissue produces a variety of inflammatory cytokines (or adipokines) that are known to modulate key mechanisms of atherogenesis. In particular, adipose tissue located on the surface of the heart surrounding large coronary arteries (i.e. epicardial perivascular adipose tissue) has been implicated in the pathogenesis of coronary artery disease. The present review outlines our current understanding of the cellular and molecular links between perivascular adipose tissue and atherosclerosis with a focus on potential mechanisms by which epicardial perivascular adipose tissue contributes to obesity-related coronary disease. The pathophysiology of perivascular adipose tissue in obesity and its influence on oxidative stress, inflammation, endothelial dysfunction and vascular reactivity is addressed. In addition, the contribution of specific epicardial perivascular adipose-derived adipokines (e.g. leptin, adiponectin) to the initiation and expansion of coronary disease is also highlighted. Finally, future investigative goals are discussed with an emphasis on indentifying novel therapeutic targets and disease markers within perivascular adipose tissue. This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.