Abstract 662: Perivascular Adipose Tissue-derived Prostaglandins Constrict Vessel

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Lin Chang ◽  
Luis Villacota ◽  
Chunyan Dou ◽  
Eugene Chen ◽  
Jifeng Zhang
Keyword(s):  
Adipose Tissue ◽  
Carotid Artery ◽  
Contractile Properties ◽  
Mesenteric Arteries ◽  
Contractile Property ◽  
Dependent Manner ◽  
Wild Type ◽  
Perivascular Adipose Tissue ◽  
Cox Inhibitor ◽  
Dose Dependent

Background: Perivascular adipose tissue (PVAT) is associated with reduced response to vasoconstricting agents in the murine vasculature and also in human small arteries, and this anti-contractile effect is reduced in subjects with metabolic syndrome. However, it was suggested that other vasoconstrictors released from PVAT such as leptin or Angiotensin II causes vasoconstriction, suggesting that PVAT has contractile properties as well. Here we show that prostaglandins and adrenalin signaling derived from PVAT contribute to contractile properties of PVAT. Results: The effect of donor PVAT on the vascular tone was evaluated in carotid, thoracic and mesenteric arteries using a myograph chamber in which the PVAT surrounding the tested vessel was completely removed. Fifteen mg of minced PVAT (size of ∼1 mm 3 ) from donor C57BL/6J mice into the myograph chamber results in mild vasoconstriction (1.52±0.6mN) on carotid artery rings. This contractile property of PVAT is effective on vessel rings obtained from the thoracic aorta and mesenteric artery as well. PVAT from leptin knockout mice used as a donor causes vasoconstriction similar to that of wild-type mice (1.55±0.5mN leptin knockout vs. 1.52±0.6mN C57BL/6J mice). Pre-incubation of vessel rings with increasing concentrations of nonspecific COX inhibitor (10 -9 M to 10 -6 M indomethacin) inhibits PVAT-induced constriction in a dose-dependent manner (1.55±0.7mN, 1.41±0.6mN, 1.23±0.5mN, 0.95±0.4mN, 0.56±0.6mN, respectively), suggesting that PVAT-derived prostaglandin are responsible for vascular constriction. Similarly, pre-incubation with alpha-adrenergic receptor antagonists blocks PVAT-dependent vasoconstriction. Carotid artery responses to a series of 10 -7 M phenylephrine (PE) addition/wash out (5x) experiments in the myograph chamber cause alpha-adrenergic desensitization. However, in the presence of donor PVAT, carotid arteries have preserved maximal contraction after 5 rounds of PE addition/wash out experiments. Conclusion: Our studies indicate that PVAT-derived prostaglandins rather than leptin or other adipokines cause vasoconstriction and reduce vascular alpha-adrenergic desensitization.

scholarly journals Perivascular adipose tissue-derived adiponectin activates BKCa channels to induce anticontractile responses

2013 ◽  
Vol 304 (6) ◽  
pp. H786-H795 ◽  
Author(s):  
Fiona M. Lynch ◽  
Sarah B. Withers ◽  
Zhihong Yao ◽  
Matthias E. Werner ◽  
Gill Edwards ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Knockout Mice ◽  
Wild Type Mouse ◽  
Mesenteric Arteries ◽  
Wild Type ◽  
Bkca Channels ◽  
Perivascular Adipose Tissue ◽  
Contractile Responses ◽  
Small Arteries ◽  
Oxide Synthase

This study aims to identify the potential mechanisms by which perivascular adipose tissue (PVAT) reduces tone in small arteries. Small mesenteric arteries from wild-type and large-conductance Ca2+-activated K+ (BKCa) channel knockout mice were mounted on a wire myograph in the presence and absence of PVAT, and contractile responses to norepinephrine were assessed. Electrophysiology studies were performed in isolated vessels to measure changes in membrane potential produced by adiponectin. Contractile responses from wild-type mouse small arteries were significantly reduced in the presence of PVAT. This was not observed in the presence of a BKCa channel inhibitor or with nitric oxide synthase (NOS) inhibition or in BKCa or adiponectin knockout mice. Solution transfer experiments demonstrated the presence of an anticontractile factor released from PVAT. Adiponectin-induced vasorelaxation and hyperpolarization in wild-type arteries were not evident in the absence of or after inhibition of BKCa channels. PVAT from BKCa or adiponectin knockout mice failed to elicit an anticontractile response in wild-type arteries. PVAT releases adiponectin, which is an anticontractile factor. Its effect on vascular tone is mediated by activation of BKCa channels on vascular smooth muscle cells and adipocytes and by endothelial mechanisms.

Bradykinin stimulates ceramide production by activating specific BK-B1receptor in rat small artery

2002 ◽  
Vol 282 (1) ◽  
pp. H175-H183 ◽  
Author(s):  
Leonard Kleine ◽  
Gele Liu ◽  
Normand Leblanc ◽  
Richard L. Hébert
Keyword(s):  
Vascular Tone ◽  
Functional Change ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Small Artery ◽  
Mediated Effects ◽  
Ceramide Generation ◽  
Dose Dependent ◽  
Hydrolysis Of ◽  
Ceramide Production

Bradykinin (BK), a proinflammatory factor and vasodilator, causes functional change of the small artery. However, it is not clear whether any of these changes induced by BK are mediated by N-acetyl-d-sphingosine (ceramide). Therefore, we investigated whether BK affects the hydrolysis of sphingomyelin and generation of ceramide in the intact rat small artery. Our results suggest that BK induces sphingomyelin hydrolysis and increases ceramide production in a time- and dose-dependent manner. Relative to controls, BK causes a 50% decrease in sphingomyelin levels. Ceramide levels increase in response to BK with the highest level being obtained with 10−8M BK as well as similar amounts of ceramide are generated when exogenous sphingomyelinase (SMase) is added. We then determined which of the two BK receptors (BK-B1antagonist Lys-Des-Arg9-Leu8-BK or the BK-B2antagonist HOE-140) are implicated in the BK-induced generation of ceramide. The BK-B2antagonist did not alter the effect of BK on ceramide generation, whereas the BK-B1antagonist blocked the BK-induced production of ceramide. Although ceramide had no effect on KCl-induced constrictions, ceramide dilated preconstricted (phenylephrine) small pressurized rat mesenteric arteries by ∼40%. These results suggest that the activation of the BK-B1receptor mediates the BK-induced activation of SMase and of the production of ceramide. In conclusion, BK-mediated effects on vascular tone may be due, at least in part, to the increased production of ceramide.

scholarly journals Perivascular Adipose Tissue-Enhanced Vasodilation in Metabolic Syndrome Rats by Apelin and N-Acetyl–l-Cysteine-Sensitive Factor(s)

2018 ◽  
Vol 20 (1) ◽  
pp. 106 ◽  
Author(s):  
Satomi Kagota ◽  
Kana Maruyama-Fumoto ◽  
Saki Iwata ◽  
Miho Shimari ◽  
Shiori Koyanagi ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Mrna Level ◽  
Receptor Activation ◽  
At1 Receptor ◽  
Mesenteric Arteries ◽  
Mrna Levels ◽  
Perivascular Adipose Tissue ◽  
Age Related ◽  
Sensitive Factor

Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related changes and responsible factor(s) involved in the enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Acetylcholine- and sodium nitroprusside-induced relaxations of isolated arteries were greater with PVAT than without PVAT at 17 and 20 weeks of age (wks), and as expected, this enhancement by the presence of PVAT disappeared at 23 wks. PVAT mRNA levels of angiotensin II type 1 (AT1) receptor-associated protein was less and AT1 receptor was unchanged at 23 wks when compared to 20 wks. At 20 wks, the enhanced acetylcholine-induced relaxation by the presence of PVAT was inhibited by N-acetyl-l-cysteine (NAC). Acetylcholine-induced relaxation of arteries without PVAT was increased in the presence of exogenously added apelin. PVAT mRNA level of apelin was higher in SHRSP.ZF than in control Wistar-Kyoto rats, and the level was decreased with aging. These results suggest that AT1 receptor activation in PVAT, and changes in the regulation of apelin and a NAC-sensitive factor are related to the age-dependent deterioration of the vasodilation enhancing effects of mesenteric arterial PVAT in SHRSP.ZF.

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

scholarly journals Lipopolysaccharide biosynthesis-related genes are required for colony pigmentation of Porphyromonas gingivalis

Microbiology ◽  
2009 ◽  
Vol 155 (4) ◽  
pp. 1282-1293 ◽  
Author(s):  
Keiko Sato ◽  
Nobuo Kido ◽  
Yukitaka Murakami ◽  
Charles I. Hoover ◽  
Koji Nakayama ◽  
...  
Keyword(s):  
Cell Surface ◽  
Porphyromonas Gingivalis ◽  
Dependent Manner ◽  
Wild Type ◽  
Gene Encoding ◽  
Lipopolysaccharide Biosynthesis ◽  
Ladder Pattern ◽  
Surface Polysaccharides ◽  
Culture Supernatants ◽  
Dose Dependent

The periodontopathic bacterium Porphyromonas gingivalis forms pigmented colonies when incubated on blood agar plates as a result of accumulation of μ-oxo haem dimer on the cell surface. Gingipain–adhesin complexes are responsible for production of μ-oxo haem dimer from haemoglobin. Non-pigmented mutants (Tn6-5, Tn7-1, Tn7-3 and Tn10-4) were isolated from P. gingivalis by Tn4351 transposon mutagenesis [Hoover & Yoshimura (1994), FEMS Microbiol Lett 124, 43–48]. In this study, we found that the Tn6-5, Tn7-1 and Tn7-3 mutants carried Tn4351 DNA in a gene homologous to the ugdA gene encoding UDP-glucose 6-dehydrogenase, a gene encoding a putative group 1 family glycosyltransferase and a gene homologous to the rfa gene encoding ADP heptose-LPS heptosyltransferase, respectively. The Tn10-4 mutant carried Tn4351 DNA at the same position as that for Tn7-1. Gingipain activities associated with cells of the Tn7-3 mutant (rfa) were very weak, whereas gingipain activities were detected in the culture supernatants. Immunoblot and mass spectrometry analyses also revealed that gingipains, including their precursor forms, were present in the culture supernatants. A lipopolysaccharide (LPS) fraction of the rfa deletion mutant did not show the ladder pattern that was usually seen for the LPS of the wild-type P. gingivalis. A recombinant chimera gingipain was able to bind to an LPS fraction of the wild-type P. gingivalis in a dose-dependent manner. These results suggest that the rfa gene product is associated with biosynthesis of LPS and/or cell-surface polysaccharides that can function as an anchorage for gingipain–adhesin complexes.

scholarly journals Uric Acid Secretion from Adipose Tissue and Its Increase in Obesity

2013 ◽  
Vol 288 (38) ◽  
pp. 27138-27149 ◽  
Author(s):  
Yu Tsushima ◽  
Hitoshi Nishizawa ◽  
Yoshihiro Tochino ◽  
Hideaki Nakatsuji ◽  
Ryohei Sekimoto ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Uric Acid ◽  
Acid Secretion ◽  
Acid Production ◽  
Culture Medium ◽  
Dependent Manner ◽  
Obese Mice ◽  
Subsequent Increase ◽  
Dose Dependent ◽  
Uric Acid Secretion

Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity.

scholarly journals Choline Induces Transcriptional Repression and Proteasomal Degradation of the Malarial Phosphoethanolamine Methyltransferase

2007 ◽  
Vol 6 (9) ◽  
pp. 1618-1624 ◽  
Author(s):  
William Harold Witola ◽  
Choukri Ben Mamoun
Keyword(s):  
Transcriptional Repression ◽  
Morphological Changes ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Wild Type ◽  
Active Synthesis ◽  
Rapid Multiplication ◽  
Gene And Protein Expression ◽  
Transgenic Parasites ◽  
Dose Dependent

ABSTRACT During its intraerythrocytic life cycle, the malaria parasite Plasmodium falciparum undergoes dramatic metabolic and morphological changes and multiplies to produce up to 36 new daughter parasites. This rapid multiplication of the parasite requires an active synthesis of new membranes. The major component of these membranes, phosphatidylcholine, is synthesized via two metabolic routes, the CDP-choline pathway, which uses host choline as a precursor, and the plant-like serine decarboxylase-phosphoethanolamine methyltransferase (SDPM) pathway, which uses host serine as a precursor. Here we provide evidence indicating that the activity of the SDPM pathway is regulated by the CDP-choline precursor, choline. We show that the phosphoethanolamine methyltransferase, Pfpmt, a critical enzyme in the SDPM pathway, is down-regulated at the transcriptional level as well as targeted for degradation by the proteasome in the presence of choline. Transcript analysis revealed that PfPMT transcription is repressed by choline in a dose-dependent manner. Immunoblotting, pulse-chase experiments, and immunoprecipitation studies demonstrated that Pfpmt degradation occurs not only in wild-type but also in transgenic parasites constitutively expressing Pfpmt. The proteasome inhibitor bortezomib inhibited choline-mediated Pfpmt degradation. These data provide the first evidence for metabolite-mediated transcriptional and proteasomal regulation in Plasmodium and will set the stage for the use of this system for conditional gene and protein expression in this organism.

scholarly journals Genetic or Enzymatic Disruption of Aromatase Inhibits the Growth of Ectopic Uterine Tissue

2002 ◽  
Vol 87 (7) ◽  
pp. 3460-3466 ◽  
Author(s):  
Zongjuan Fang ◽  
Sijun Yang ◽  
Bilgin Gurates ◽  
Mitsutoshi Tamura ◽  
Evan Simpson ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Mouse Model ◽  
Lesion Size ◽  
Dependent Manner ◽  
Wild Type ◽  
Uterine Tissue ◽  
Abdominal Organs ◽  
Letrozole Treatment ◽  
Key Enzyme ◽  
Dose Dependent

Aromatase P450 (P450arom) is the key enzyme for the biosynthesis of estrogen that is essential for the growth of human endometriosis, a pathology characterized by endometrium-like tissue on the peritoneal surfaces of abdominal organs manifest by pelvic pain and infertility. Surgically transplanted autologous uterine tissue to ectopic sites on the peritoneum in mice has been used as an animal model to study endometriosis. Using this mouse model, we evaluated the roles of the P450arom gene and aromatase enzyme activity in the growth of endometriosis represented by ectopic uterine tissues in mice. Endometriosis was induced surgically in the following groups of mice: 1) untreated transgenic mice with disrupted P450arom gene (ArKO); 2) ArKO mice treated with systemic estrogen; 3) untreated wild-type (WT) mice; 4) WT mice treated with estrogen; 5) WT mice treated with the aromatase inhibitor, letrozole; and 6) WT mice treated with letrozole and estrogen. Each group contained eight mice; +/+ littermates of ArKO mice were used as WT controls. Treatment with estrogen increased the size of ectopic uterine tissues in ArKO and WT mice significantly. The ectopic uterine lesions in untreated and estrogen-treated ArKO mice were strikingly smaller than those in untreated and estrogen-treated WT controls, respectively. Systemic treatment of WT mice with letrozole significantly decreased the lesion size in a dose-dependent manner. The addition of estrogen to letrozole treatment increased the ectopic lesion size, although these lesions were significantly smaller than those in mice treated with estrogen only. As tissue controls, the effects of these conditions on normally located (eutopic) uterine tissue were evaluated. The effects of disruption of the P450arom gene and treatments with letrozole and estrogen seemed to be more profound on ectopic tissues, suggesting that ectopic tissues might be more sensitive to estrogen for growth. We conclude that both an intact P450arom gene and the presence of aromatase enzyme activity are essential for the growth of ectopic uterine tissue in a mouse model of endometriosis.

Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1456-1463 ◽  
Author(s):  
Karen L. Jones ◽  
Sascha C. Hughan ◽  
Sacha M. Dopheide ◽  
Richard W. Farndale ◽  
Shaun P. Jackson ◽  
...  
Keyword(s):  
Cell Adhesion Molecule ◽  
Collagen Matrix ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Wild Type ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1 ◽  
Dose Dependent ◽  
Deficient Mice ◽  
Endothelial Cell Adhesion

The functional importance of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in platelets is unclear. Because PECAM-1 represents a newly assigned immunoglobulin–ITIM superfamily member expressed on the surface of platelets, it was hypothesized that it may play an important regulatory role in modulating ITAM-bearing receptors such as collagen (GP)VI receptor and FcγRIIA. To examine the functional role of PECAM-1 in regulating platelet-collagen interactions, 2 different approaches were applied using recombinant human PECAM-1–immunoglobulin chimeras and platelets derived from PECAM-1–deficient mice. Stimulation of platelets by collagen-, (GP)VI-selective agonist, collagen-related peptide (CRP)–, and PECAM-1–immunoglobulin chimera induced tyrosine phosphorylation of PECAM-1 in a time- and dose-dependent manner. Activation of PECAM-1 directly through the addition of soluble wild-type PECAM-1–immunoglobulin chimera, but not mutant K89A PECAM-1–immunoglobulin chimera that prevents homophilic binding, was found to inhibit collagen- and CRP-induced platelet aggregation. PECAM-1–deficient platelets displayed enhanced platelet aggregation and secretion responses on stimulation with collagen and CRP, though the response to thrombin was unaffected. Under conditions of flow, human platelet thrombus formation on a collagen matrix was reduced in a dose-dependent manner by human PECAM-1–immunoglobulin chimera. Platelets derived from PECAM-1–deficient mice form larger thrombi when perfused over a collagen matrix under flow at a shear rate of 1800 seconds−1 compared to wild-type mice. Collectively, these results indicate that PECAM-1 serves as a physiological negative regulator of platelet-collagen interactions that may function to negatively limit growth of platelet thrombi on collagen surfaces.

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