scholarly journals Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo

2019 ◽  
Vol 56 (6) ◽  
pp. 320-332
Author(s):  
Sophie N. Saxton ◽  
Sarah B. Withers ◽  
Jakob Nyvad ◽  
Aleksandra Mazur ◽  
Vladimir Matchkov ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Vascular Tone ◽  
Perivascular Adipose Tissue

Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kaivan Khavandi ◽  
Adam Greenstein ◽  
Sarah Withers ◽  
Kazuhiko Sonoyama ◽  
Sarah Lewis ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Vascular Tone ◽  
Tnf Alpha ◽  
Perivascular Adipose Tissue ◽  
The Metabolic Syndrome ◽  
Adipocyte Cell ◽  
Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

P735Interleukin-33 induced eosinophilia restores perivascular adipose tissue function in obesity

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Saxton ◽  
R J Potter ◽  
S B Withers ◽  
R Grencis ◽  
A M Heagerty
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Plasma Insulin ◽  
Vascular Tone ◽  
Mesenteric Arteries ◽  
Obese Mice ◽  
High Fat ◽  
Perivascular Adipose Tissue

Abstract Background/Purpose Perivascular adipose tissue (PVAT) is essential in the modulation of vascular tone. Recently we have shown that resident eosinophils play a vital role in regulating PVAT function. In obesity, eosinophil numbers are reduced and PVAT anticontractile function is lost, resulting in increased vascular tone, which will contribute to development of hypertension and type-2 diabetes. Evidence suggests that eosinophilia resulting from parasitic infection may be useful in improving glucose tolerance; therefore, we investigated the effects of eosinophilia on PVAT function in health and obesity. Methods Control mice and a high fat fed mouse model of obesity were administered intraperitoneal injections of interleukin-33 (IL-33, 0.1μg) over a five day period. Blood pressure, blood glucose and plasma insulin were measured and compared with un-injected control and obese mice. Wire myography was used to assess the vascular contractility of mesenteric arteries (<250μm, +/− PVAT) from both injected and un-injected control and obese mice in response to noradrenaline. ELISAs and immunohistochemistry were used to examine eosinophil numbers. Results High fat feeding induced significant elevations in blood pressure, blood glucose and plasma insulin, which were reduced using IL-33 injections. Eosinophilia was confirmed in blood plasma using an eosinophil cationic protein ELISA. Using wire myography, mesenteric arteries from control mice PVAT exerted an anticontractile effect on the vessels, which was enhanced in control mice injected with IL-33. In obese mice, the PVAT anticontractile effect was lost, but was restored in IL-33 injected obese mice. Using immunohistochemistry, we confirm that eosinophils numbers in PVAT were reduced in obesity and increased in IL-33 treated PVAT. Conclusions IL-33 injections induced eosinophilia in both control and obese mice. IL-33 treatment restored PVAT function in obesity, and enhanced the anticontractile function of PVAT in healthy animals. In addition, only five consecutive injections of IL-33 reversed development of hypertension and type-2 diabetes in obese mice. These data suggest that IL-33 induced eosinophilia presents a novel approach to treatment of hypertension and type-2 diabetes in obesity. Acknowledgement/Funding British Heart Foundation

Endogenous hydrogen sulfide in perivascular adipose tissue: role in the regulation of vascular tone in physiology and pathology

2013 ◽  
Vol 91 (11) ◽  
pp. 889-898 ◽  
Author(s):  
Jerzy Bełtowski
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hydrogen Sulfide ◽  
Vascular Tone ◽  
Compensatory Mechanism ◽  
Short Term ◽  
Insulin Sensitizer ◽  
Perivascular Adipose Tissue ◽  
S Oxidation ◽  
Lipophilic Statin

Hydrogen sulfide (H2S) is synthesized from l-cysteine by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE), and is enzymatically metabolized in mitochondria by sulfide:quinone oxidoreductase (SQR). Recent studies have indicated that H2S is synthesized by CSE in perivascular adipose tissue (PVAT), and is responsible for the anticontractile effect of PVAT on adjacent vessels. The lipophilic statin atorvastatin increases PVAT-derived H2S by suppressing its mitochondrial oxidation; the effect that results from statin-induced depletion of ubiquinone. Experimental obesity induced by a highly palatable diet has a time-dependent effect on H2S in PVAT. Adipose tissue hypoxia suppresses H2S oxidation and increases its level in short-term obesity not associated with insulin resistance. In contrast, in long-term obesity, insulin resistance and (or) hyperinsulinemia result in the down-regulation of CSE and H2S deficiency, which is corrected by treatment with the insulin sensitizer rosiglitazone. In addition, cannabinoid CB1 receptor agonist administered for 2 weeks increases H2S by impairing mitochondria biogenesis. This indicates that the rate of mitochondrial H2S oxidation plays an important role in the regulation of H2S level in PVAT. Up-regulation of H2S signaling in short-term obesity and (or) by elevated endocannabinoids may be a compensatory mechanism that maintains vascular tone, despite endothelial dysfunction.

scholarly journals Role of Perivascular Adipose Tissue–Derived Methyl Palmitate in Vascular Tone Regulation and Pathogenesis of Hypertension

Circulation ◽  
2011 ◽  
Vol 124 (10) ◽  
pp. 1160-1171 ◽  
Author(s):  
Yuan-Chieh Lee ◽  
Hsi-Hsien Chang ◽  
Chih-Lung Chiang ◽  
Chin-Hung Liu ◽  
Jih-I Yeh ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Methyl Palmitate ◽  
Vascular Tone ◽  
Perivascular Adipose Tissue

scholarly journals Aging Affects KV7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone

2021 ◽  
Vol 12 ◽  
Author(s):  
Yibin Wang ◽  
Fatima Yildiz ◽  
Andrey Struve ◽  
Mario Kassmann ◽  
Lajos Markó ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Vascular Function ◽  
Vascular Tone ◽  
Mesenteric Arteries ◽  
Aging Effects ◽  
Perivascular Adipose Tissue ◽  
Kcnq Channels ◽  
Age Related ◽  
Cardiovascular Morbidity And Mortality

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.

PS9 - 14. Perivascular adipose tissue characteristics are related with in vivo microvascular and metabolic insulin sensitivity

2013 ◽  
Vol 11 (4) ◽  
pp. 193-193
Author(s):  
Rick I. Meijer ◽  
Michiel P. de Boer ◽  
Etto C. Eringa ◽  
Donald L. van der Peet ◽  
Erik van Poelgeest ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Perivascular Adipose Tissue ◽  
Tissue Characteristics

Abstract 307: The Presence of an Adrenergic System in Perivascular Adipose Tissue

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nadia Ayala-Lopez ◽  
William F Jackson ◽  
James N Wilson ◽  
Robert Burnett ◽  
Marisa Martini ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Vascular Tone ◽  
Glyoxylic Acid ◽  
Specific Inhibitor ◽  
Norepinephrine Transporter ◽  
Adrenergic System ◽  
Substrate Uptake ◽  
Pressure Regulation ◽  
Perivascular Adipose Tissue ◽  
Health And Disease

Perivascular adipose tissue (PVAT) is under recognized for its importance in blood pressure regulation. Visceral adipocytes reportedly contain catecholamines. Adipocytes in PVAT are directly adjacent to the blood vessels they surround and therefore the production, release and/or reuptake of catecholamines may significantly affect vascular tone. We hypothesize that an adrenergic system is present in PVAT. Glyoxylic acid staining revealed the presence of catecholamines in the cytosol of mesenteric PVAT adipocytes. Dopamine (DA), norepinephrine (NE) and epinephrine were quantified by HPLC in rat aortic PVAT, brown fat, mesenteric PVAT and retroperitoneal fat with NE being the most abundant at concentrations of 731.9, 815.0, 668.7 and 73.2 ng/g from each tissue, respectively. Two key enzymes in catecholamine synthesis; tyrosine hydroxylase and dopamine β-hydroxylase, were located to PVAT adipocytes by immunohistochemistry. The norepinephrine transporter (NET) was detected on mesenteric PVAT adipocytes by confocal microscopy using ASP+ (2μM), a fluorescent NET substrate. Uptake of ASP+ was blocked by the NET specific inhibitor nisoxetine (10μM) (see figure). These data show that PVAT contains all of the elements of an adrenergic system and may contribute to vascular and adipose function in health and disease.

scholarly journals JNK2 in myeloid cells impairs insulin’s vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction

2019 ◽  
Vol 317 (2) ◽  
pp. H364-H374
Author(s):  
Rick I. Meijer ◽  
Femke P. M. Hoevenaars ◽  
Erik H. Serné ◽  
John S. Yudkin ◽  
Tom J. A. Kokhuis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Marrow ◽  
Adipose Tissue ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Inflammatory Cells ◽  
Western Diet ◽  
Perivascular Adipose Tissue ◽  
Muscle Perfusion

Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2−/− bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo. NEW & NOTEWORTHY We demonstrate that in the earliest phase of weight gain, changes in perivascular adipose tissue in muscle impair insulin-stimulated muscle perfusion. The hallmark of these changes is infiltration by inflammatory cells. Deletion of JNK2 from the bone marrow restores the function of perivascular adipose tissue to enhance insulin’s vasodilator effects in muscle, showing that the bone marrow contributes to regulation of muscle perfusion.

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