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?3 -Adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived NO and vascular relaxation in small arteries.

ABSTRACT: BACKGROUND AND PURPOSE:In response to noradrenaline, healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arterial tissue. Organ bath solution transfer experiments have demonstrated the release of PVAT-derived relaxing factors that mediate this function. The present studies were designed to investigate the mechanism responsible for the noradrenaline-induced PVAT anticontractile effect. EXPERIMENTAL APPROACH:In vitro rat small arterial contractile function was assessed using wire myography in the presence and absence of PVAT and the effects of sympathomimetic stimulation on the PVAT environment explored using Western blotting and assays of organ bath buffer. KEY RESULTS:PVAT elicited an anticontractile effect in response to noradrenaline but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the ?3 -adrenoceptor agonist, CL-316243, reduced the vasoconstrictor effect of phenylephrine but not noradrenaline. Kv 7 channel inhibition using XE 991 reversed the noradrenaline-induced anticontractile effect in exogenously applied PVAT studies. Adrenergic stimulation of PVAT with noradrenaline and CL-316243, but not phenylephrine, was associated with increased adipocyte-derived NO production, and the contractile response to noradrenaline was augmented following incubation of exogenous PVAT with L-NMMA. PVAT from eNOS-/- mice had no anticontractile effect. Assays of adipocyte cAMP demonstrated an increase with noradrenaline stimulation implicating G?s signalling in this process. CONCLUSIONS AND IMPLICATIONS:We have shown that adipocyte-located ?3 -adrenoceptor stimulation leads to activation of G?s signalling pathways with increased cAMP and the release of adipocyte-derived NO. This process is dependent upon Kv 7 channel function. We conclude that adipocyte-derived NO plays a central role in anticontractile activity when rodent PVAT is stimulated by noradrenaline.

SUBMITTER: Bussey CE

PROVIDER: S-EPMC6109217 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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β<sub>3</sub> -Adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived NO and vascular relaxation in small arteries.

Bussey Charlotte E CE Withers Sarah B SB Saxton Sophie N SN Bodagh Neil N Aldous Robert G RG Heagerty Anthony M AM

British journal of pharmacology 20180810 18

<h4>Background and purpose</h4>In response to noradrenaline, healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arterial tissue. Organ bath solution transfer experiments have demonstrated the release of PVAT-derived relaxing factors that mediate this function. The present studies were designed to investigate the mechanism responsible for the noradrenaline-induced PVAT anticontractile effect.<h4>Experimental approach</h4>In vitro rat small arterial contr ...[more]

PMID: 29980164

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Project description:Background and purposeIn small arteries, small conductance Ca²?-activated K? channels (SK(Ca)) and intermediate conductance Ca²?-activated K? channels (IK(Ca)) restricted to the vascular endothelium generate hyperpolarization that underpins the NO- and PGI?-independent, endothelium-derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IK(Ca) channels can be negatively regulated by PKA, we investigated whether ?-adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation.Experimental approachRat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell [Ca²?]i , mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording.Key resultsIntraluminal perfusion of ?-adrenoceptor agonists inhibited endothelium-dependent dilatation to ACh (1 nM-10 ?M) without modifying the associated changes in endothelial cell [Ca²?]i . The inhibitory effect of ?-adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the ?-adrenoceptor antagonists propranolol (non-selective), atenolol (??) or the PKA inhibitor KT-5720, but remained unaffected by ICI 118 551 (??) or glibenclamide (ATP-sensitive K? channels channel blocker). Endothelium-dependent hyperpolarization to ACh was also inhibited by ?-adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IK(Ca) {with 1 ?M 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34)}, but not SK(Ca) (50 nM apamin) channels prevented ?-adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.Conclusions and implicationsIn resistance arteries, endothelial cell ??-adrenoceptors link to inhibit endothelium-dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IK(Ca) channels and may be one consequence of raised circulating catecholamines.

Project description:Objective- Perivascular adipose tissue (PVAT) contains an independent adrenergic system that can take up, metabolize, release, and potentially synthesize the vasoactive catecholamine norepinephrine. Norepinephrine has been detected in PVAT, but the mechanism of its protection within this tissue is unknown. Here, we investigate whether PVAT adipocytes can store norepinephrine using VMAT (vesicular monoamine transporter). Approach and Results- High-performance liquid chromatography identified norepinephrine in normal male Sprague Dawley rat aortic, superior mesenteric artery, and mesenteric resistance vessel PVATs, and retroperitoneal fat. Real-time polymerase chain reaction revealed VMAT1 and VMAT2 mRNA expression in the adipocytes and stromal vascular fraction of mesenteric resistance vessel PVAT. Immunofluorescence demonstrated the presence of VMAT1 and VMAT2, and the colocalization of VMAT2 with norepinephrine, in the cytoplasm of adipocytes in mesenteric resistance vessel PVAT. A protocol was developed to capture real-time uptake of Mini 202-a functional and fluorescent VMAT probe-in live rat PVAT adipocytes. Mini 202 was taken up by freshly isolated and differentiated adipocytes from mesenteric resistance vessel PVAT and adipocytes from thoracic aortic and superior mesenteric artery PVATs. In adipocytes freshly isolated from mesenteric resistance vessel PVAT, addition of rose bengal (VMAT inhibitor), nisoxetine (norepinephrine transporter inhibitor), or corticosterone (organic cation 3 transporter inhibitor) significantly reduced Mini 202 signal. Immunofluorescence supports that neither VMAT1 nor VMAT2 is present in retroperitoneal adipocytes, suggesting that PVAT adipocytes may be unique in storing norepinephrine. Conclusions- This study supports a novel function of PVAT adipocytes in storing amines in a VMAT-dependent manner. It provides a foundation for future studies exploring the purpose and mechanisms of norepinephrine storage by PVAT in normal physiology and obesity-related hypertension.

Project description:BackgroundDiabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson's disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known.MethodsWe combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood-brain barrier leakage, and the interaction between microvessels and microglia in the striatum.ResultsDifferent degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology.ConclusionThis study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes.

Dataset Information

?3 -Adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived NO and vascular relaxation in small arteries.

Publications

β<sub>3</sub> -Adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived NO and vascular relaxation in small arteries.

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