A M Heagerty

The University of Manchester, Manchester, England, United Kingdom

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Publications (272)1958.34 Total impact

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    ABSTRACT: sec> Objective Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists which is lost in diabetes and hypertension. Solution transfer experiments have demonstrated the existence of an adipocyte-derived relaxing factor (s) that mediates anticontractile function; however controversy exists surrounding the release mechanisms and its identity. This study aimed to elucidate the pathways involved in the anticontractile response to adrenergic and non-adrenergic agonists. Methods The effects of PVAT on the contractility of isolated rat mesenteric arteries were investigated using wire myography. Concentration-response curves were generated to noradrenaline, phenylephrine or serotonin (1 × 10–5–3 × 10–9 mol.l–1) following 30 min incubation with the ß3-agonist, CL-316,243 (10 µmol.l–1); ß3-antagonist, SR59230A (30 µmol.l–1); NOS inhibitor, L-NMMA (100 µmol.l–1); BKCa channel inhibitor, iberiotoxin (100nmol.l-1) or the KCNQ inhibitor, XE 991 (10 µmol.l–1). Results and conclusions PVAT elicited an anticontractile effect in response to both noradrenaline and serotonin, but not phenylephrine (noradrenaline: P<0.01, serotonin: P<0.05, phenylephrine: P=0.8321). In vessels with PVAT, CL-316,243 abrogated the vasoconstrictor effect of phenylephrine (P<0.01), but not noradrenaline (P=0.9057). Moreover, incubation with SR59230A potentiated the response to noradrenaline in vessels with PVAT (P<0.05) suggesting a role for 3-adrenergic signalling in mediating noradrenaline-induced PVAT function. The presence of L-NMMA produced an increase in the vasoconstrictor action of noradrenaline in vessels with PVAT (P<0.05) indicating that nitric oxide plays a role in the adrenergic-dependent PVAT anticontractile effect. This was reaffirmed by observations of 3-adrenoceptor and eNOS expression within PVAT using western blotting. ß3-adrenoceptor manipulation did not alter the serotonin-induced PVAT anticontractile effect (SR 59230A: Incubation with iberiotoxin abrogated PVAT function in response to noradrenaline (P < 0.001) and serotonin (P < 0.001) suggesting involvement of BKCa channel activation in both signalling pathways. However, the presence of XE 991 reversed the noradrenaline-induced PVAT anticontractile effect (P < 0.001) but had no effect on the serotonin-induced effect (P = 0.9417) indicating a role for KCNQ channel activation in the 3-dependent anticontractile effect. Overall, this study indicates that PVAT exerts an agonist-dependent anticontractile effect via distinct mechanisms potentially leading release of a number of adipocyte-derived relaxing factors. </sec
    Heart (British Cardiac Society) 06/2015; 101(Suppl 4):A99-A100. DOI:10.1136/heartjnl-2015-308066.176 · 6.02 Impact Factor
  • Sophie Saxton · Amy Watkins · Anthony Heagerty · Sarah Withers
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    ABSTRACT: sec> Introduction There is considerable evidence to implicate over-activity of the sympathetic nervous system during obesity and the subsequent development of metabolic syndrome and type 2 diabetes. It has been suggested that these conditions are dependent upon changes in small artery function. Healthy perivascular fat exerts an anti-contractile effect on circulation which is lost in obesity. Therefore it was decided to examine the effects of sympathetic nerve stimulation on perivascular adipose tissue (PVAT) function. The hypothesis to be tested was that an anti-contractile factor is released from PVAT as a result of sympathetic nerve stimulation. Methods The frequency-stimulation profiles (0.1–30 Hz) of murine mesenteric arteries (<200 µM), +/-PVAT, were characterised using wire myography at various voltages (5–30 V). The accepted test for neural stimulation using 1 µM tetrodotoxin (TTX) was performed, and 1.46 µM 6-hydroxydopamine (6-OHDA) used to sympathetically denervate vessels +/-PVAT. Exogenous PVAT was incubated with TTX and 6-OHDA for 30 min before re-suspending in the bath. Specific adrenoceptor stimulation of PVAT function was investigated using noradrenaline, phenylephrine (both 1 × 10–9–1 × 10–5M), and CL-316,243 (10 µm). Results At 20&30V PVAT elicited an anti-contractile effect (P < 0.01); reproducible at 20V after a 15 min rest period. This effect is due to factors released from the PVAT and not due to a “barrier” effect, as application of exogenous PVAT elicits the same anti-contractile response (P < 0.05). Sympathetic denervation of whole vessels with 6-OHDA abolished all significant contractile activity, confirming that EFS at 20V innervates sympathetic nerves (P < 0.0001). PVAT incubated with TTX, demonstrated a reduced anti-contractile effect, confirming this effect to be neural and therefore physiologically relevant (P < 0.05). Exogenous PVAT pre-incubated with 6-OHDA also induced a diminished PVAT anti-contractile effect, implicating the role of sympathetic nerves in PVAT (P < 0.0001). In the noradrenaline but not phenylephrine concentration-response curve, PVAT elicits an anti-contractile response. The addition of β 3 -adrenoceptor agonist CL-316,243 to phenylephrine-constricted +PVAT vessels induced a relaxation which replicated the PVAT anti-contractile effect seen in vessels stimulated with NA (P < 0.05), indicating the role of β 3 -adrenoceptors in PVAT. Conclusions These results clearly demonstrate sympathetic nerve stimulation can provoke the release of vasodilators from PVAT. The mechanism appears to be via activation of the adipocyte membrane located β3-adrenoreceptor. Further studies will be carried out in an obese model to understand how over-stimulation leads to a down-regulation and a loss of anti-contractility possibly via β3 receptor desensitisation. </sec
    Heart (British Cardiac Society) 06/2015; 101(Suppl 4). DOI:10.1136/heartjnl-2015-308066.219 · 6.02 Impact Factor
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    ABSTRACT: In patients with obesity, there is increased inflammation with attendant oxidative stress in perivascular adipose tissue. This has functional consequences with loss of vasodilator adipokine bioavailability. Part of the inflammatory response is mediated by increased activation of the renin-angiotensin-aldosterone axis. Therefore, this study was designed to investigate whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can improve the anticontractile function of perivascular adipose tissue. Segments of rat mesenteric small artery were dissected and mounted in a wire myograph and contracted to incremental doses of norepinephrine in the presence and absence of perivascular adipose tissue and in conditions of normal oxygenation or after hypoxia and incubated with captopril or telmisartan. Vessels with perivascular adipose tissue contracted significantly less than arteries with perivascular adipose tissue removed under normal oxygenation conditions, indicating that perivascular adipose tissue exerts an anticontractile effect. Hypoxia induced a loss of this anticontractile effect which could be completely prevented with captopril or telmisartan. The in-vitro creation of a hypoxic environment can simulate the loss of anticontractile perivascular adipose tissue function seen in vivo in obese patients, and this can be prevented using inhibitors of the renin-angiotensin cascade.
    Journal of Hypertension 02/2015; 33(5). DOI:10.1097/HJH.0000000000000506 · 4.22 Impact Factor
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    Egidius H J Heerkens · Lisa Quinn · Sarah B Withers · Anthony M Heagerty
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    ABSTRACT: Human essential hypertension is characterized by eutrophic inward remodeling of the resistance arteries with little evidence of hypertrophy. Upregulation of αVβ3 integrin is crucial during this process. In order to investigate the role of focal adhesion kinase (FAK) activation in this process, the level of FAK Y397 autophosphorylation was studied in small blood vessels from young TGR(mRen2)27 animals as blood pressure rose and eutrophic inward remodeling took place. Between weeks 4 and 5, this process was completed and accompanied by a significant increase in FAK phosphorylation compared with normotensive control animals. Phosphorylated (p)FAK Y397 was coimmunoprecipitated with both β1- and β3-integrin-specific antibodies. In contrast, only a fraction (<10-fold) was coprecipitated with the β3 integrin subunit in control vessels. Inhibition of eutrophic remodeling by cRGDfV treatment of TGR(mRen2)27 rats resulted in the development of smooth-muscle-cell hypertrophy and a significant further enhancement of FAK Y397 phosphorylation, but this time with exclusive coassociation of pFAK Y397 with integrin β1. We established that phosphorylation of FAK Y397 with association with β1 and β3 integrins occurs with pressure-induced eutrophic remodeling. Inhibiting this process leads to an adaptive hypertrophic vascular response induced by a distinct β1-mediated FAK phosphorylation pattern. © 2014 S. Karger AG, Basel.
    Journal of Vascular Research 10/2014; 51(4):305-314. DOI:10.1159/000365479 · 2.44 Impact Factor
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    ABSTRACT: Perivascular adipose tissue (PVAT) has been shown by various studies to have an anti-contractile effect on the arteries it surrounds. The mechanism by which PVAT exerts its anti-contractile effect is not well understood, and is likely to involve the release of PVAT-derived relaxing factors (PVRF) such as adiponectin, that causes hyperpolarisation and relaxation of the vascular smooth muscle. The PVAT anti-contractile effect is lost in obesity, therefore understanding this mechanism is vital for creating novel treatments of obesity-related hypertension. We propose that the mechanism involves stimulation of adipocyte β3-adrenoceptors in PVAT.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A102. DOI:10.1136/heartjnl-2014-306118.181 · 6.02 Impact Factor
  • Charlotte Bussey · Sarah Withers · Gillian Edwards · Anthony Heagerty
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    ABSTRACT: Perivascular adipose tissue (PVAT) exerts an anticontractile effect that is lost in obesity. A recent study reported that bariatric surgery can reverse the damaging effects of obesity on PVAT function with accompanying reduction in systolic blood pressure. However, PVAT function has not previously been characterised following weight loss induced by caloric restriction, which is often the first line treatment for obesity. This study investigated the role of PVAT in control of vascular function in rat models of diet-induced obesity and weight loss.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A111. DOI:10.1136/heartjnl-2014-306118.202 · 6.02 Impact Factor
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    ABSTRACT: The concept that fat cells could influence the circulation and indeed cardiac function has been in existence for ≥20 years and has gained a wide interest and no less excitement as evidence has accrued to suggest that such effects may be profound enough to explain disease states, such as hypertension and metabolic changes associated with obesity and type II diabetes mellitus. This ATVB in Focus intends to examine our current knowledge in this field, and suggests mechanisms that may be responsible for normal perivascular function and how they become disordered in obesity. There is the tantalizing prospect of developing new therapeutic approaches to keep obese individuals healthy and redesignating type II diabetes mellitus as a vascular disease.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2014; 34(8). DOI:10.1161/ATVBAHA.114.303031 · 5.53 Impact Factor
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    ABSTRACT: It has been demonstrated previously that inflammation in perivascular adipose tissue (PVAT) may be implicated in vascular dysfunction. The aim of this study was to investigate the functional responses of small mesenteric arteries in a hyperphagic animal model of obesity after chronic treatment with melatonin, an endogenous hormone with antioxidant and vasculoprotective properties. Ten obese mice (ob/ob) and 10 control lean mice (CLM) were treated with melatonin 100 mg/kg per day in the drinking water for 8 weeks. Mesenteric small resistance arteries were dissected and mounted on a wire myograph and a concentration-response to norepinephrine was evaluated in vessels with intact PVAT and after PVAT was removed and in the presence of iberiotoxin, a selective blocker of BKCA channels as well as under conditions of induced hypoxia in vitro. The presence of PVAT reduced the contractile response to norepinephrine in both ob/ob and CLM; however, the effect was significantly reduced in ob/ob. The anticontractile effect of PVAT completely disappeared with iberiotoxin preincubation. After melatonin treatment, inflammation was significantly ameliorated, and the contractile response in ob/ob and CLM was significantly reduced when PVAT was removed. Anticontractile effect of PVAT that is lost in obesity can be rescued using melatonin. A reduced expression of adiponectin and adiponectin receptor was observed in perivascular fat of ob/ob, whereas significant increase was observed in ob/ob treated with melatonin. Melatonin seems to exert a protective effect on arteries from both ob/ob and CLM, counteracting the adverse effect of hypoxia and iberiotoxin.
    Journal of Hypertension 04/2014; 32(6). DOI:10.1097/HJH.0000000000000178 · 4.22 Impact Factor
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    ABSTRACT: Transforming Growth Factor-β1 (TGF-β1) has been shown unequivocally to enhance neointima formation in carotid and ileo-femoral arteries. In our previous studies, however, TGF-β1 expression in coronary arteries actually reduced neointima formation without affecting luminal loss post-angioplasty, while expression of a TGF-β1 antagonist (RIIs) in balloon-injured coronary arteries reduced luminal loss without affecting neointima formation. These observed effects may be a consequence of the mode of coronary artery gene transfer employed, but they may also represent differences in the modes of healing of coronary, carotid and ileo-femoral arteries after endoluminal injury. To help clarify whether a gene therapy strategy to antagonize TGF-β might have application within the coronary vasculature, we have investigated the effect of high-level periluminal expression of RIIs using stent-based adenovirus-mediated intra-coronary gene transfer. Porcine coronary arteries were randomised to receive a custom-made CoverStent preloaded with saline-only, or with 1x109iu of adenovirus expressing RIIs or β-galactosidase (lacZ). Vessels were analyzed 28-days post-stenting, at which time angiographic in-stent diameter was significantly greater in RIIs-treated arteries, and in-stent luminal loss significantly reduced. Computerized morphometric minimum in-stent lumen area was ≈300% greater in RIIs-exposed vessels than in lacZ or saline-only groups. This was due to significantly reduced neointima formation in the RIIs group. RIIs had no demonstrable effect on cellular proliferation or apoptosis, but greater normalized neointimal/medial collagen content was observed in RIIs-exposed arteries. These data highlight the qualitatively similar effect of TGF-β antagonism on neointima formation in injured coronary and non-coronary arteries, and suggest that since cellular proliferation is unaffected, TGF-β1 antagonism might prevent in-stent restenosis without the delayed healing that is associated with drug-eluting stents in current clinical use.
    Human gene therapy 02/2014; 25(5). DOI:10.1089/hum.2013.105 · 3.62 Impact Factor
  • Atherosclerosis; 12/2013
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    ABSTRACT: To investigate the role of cGMP dependent protein kinase (PKG) in mediating the anticontractile function of perivascular adipose tissue (PVAT) and whether its activation can rescue PVAT activity which is lost in an experimental model of inflammation. Contractile responses to norepinephrine were assessed using wire myography from small arterial segments obtained from PKG(-/-), PKG(+/+), adipo(-/-) and C57Bl6/J mice with and without PVAT during normal oxygenation and hypoxia. An anticontractile effect of PVAT was observed in control blood vessels. This was not present in arteries from PKG(-/-) or PKG(+/+) with inhibition of PKG signalling using DT-2/ODQ. Hypoxia-induced loss of PVAT function was rescued by ANP activation of PKG as there was no effect in blood vessels from PKG(-/-) mice or in the presence of DT-2. Solution transfer studies demonstrated that PKG was necessary for the normal paracrine effects of PVAT on smooth muscle and endothelium. PKG activation by ANP did not restore the absent PVAT anticontractile capacity in arteries from adiponectin(-/-) mice; however inhibition of PKG did not further abrogate this effect suggesting dysregulation of PKG signalling pathways in this model. The absence of PKG was associated with reduced adipocyte adiponectin expression. PKG plays a key role in regulating normal PVAT function both in modulating anticontractile factor release from adipocytes as well as being essential for its downstream dilator function in arterial smooth muscle.
    Cardiovascular Research 10/2013; 101(1). DOI:10.1093/cvr/cvt229 · 5.81 Impact Factor
  • Ashley S Izzard · Anthony M Heagerty
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    ABSTRACT: Intrinsic arterial myogenic function comprises the degree of constriction (myogenic tone), the arterial constriction to an increase in intraluminal pressure and vice versa (myogenic response), and forced dilation at high intraluminal pressure. Although the development of myogenic tone at 40-60 mmHg involves the influx of calcium (Ca2+) through voltage-dependent Ca2+ channels and an elevation in arterial intracellular Ca2+ (Ca2+i), myogenic responses between 60-140 mmHg involves predominantly Rho kinase (ROK)-mediated changes in Ca2+ sensitivity. In the cerebral circulation an impaired myogenic response results in impaired cerebral autoregulation and susceptibility hypertension-induced cerebral haemorrhage. An impaired cerebral artery myogenic response, due to blunted ROK mediated changes in Ca2+ sensitivity, may be a consequence of defective mechanotransduction of the intraluminal pressure stimulus; this may be a result of abnormalities in the extracellular matrix. In the coronary circulation distinctions between the mechanisms involved in the development of myogenic tone and the myogenic response have not been clearly defined. However, coronary artery myogenic tone is dependent on both Ca2+ entry through voltage -dependent Ca2+ channels and protein kinase C (PKC) activity. Impaired coronary myogenic tone has been observed in animal models of disease but the implications of these findings are currently uncertain.
    Current Vascular Pharmacology 09/2013; 12(6). DOI:10.2174/15701611113116660150 · 2.91 Impact Factor
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    ABSTRACT: Introduction The aim of this study was to investigate the effect of erythropoietin on vascular contractility using an in vitro model of hypoxia replicating the hypoxic environment of blood vessels and surrounding adipose tissue in obesity. Methods and results Pharmacological in vitro studies were carried out on small mesenteric arterial segments from male Wistar rats with and without perivascular fat and endothelium. Contractile responses were investigated by wire myography under normoxia, experimental hypoxia ± erythropoietin and l-NNA. Perivascular fat exerted an anticontractile effect which was lost following the induction of experimental hypoxia. Erythropoietin prevented the loss of the anticontractile capacity when vessels were incubated for one hour before the induction of hypoxia or throughout the period of hypoxia; this was found to be independent of the function of perivascular fat, as fat denuded arteries had a similar reduction in contractility (artery no fat + hypoxia vs. artery no fat + hypoxia + erythropoietin). The mechanism by which erythropoietin was exerting its effect was found to be partially endothelium dependent and associated with an increase of nitric oxide bioavailability as nitric oxide synthase inhibition prevented the effect. Conclusions Whilst erythropoietin is working downstream from perivascular fat, it is possible that it may be therapeutically useful in obesity when hypoxia and inflammation reduce the normal activity of perivascular fat.
    Journal of cardiovascular disease research 09/2013; DOI:10.1016/j.jcdr.2013.08.002
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    ABSTRACT: IMPORTANCE Type 2 diabetes mellitus and associated chronic kidney disease (CKD) have become major public health problems. Little is known about the influence of diet on the incidence or progression of CKD among individuals with type 2 diabetes. OBJECTIVE To examine the association between (healthy) diet, alcohol, protein, and sodium intake, and incidence or progression of CKD among individuals with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS All 6213 individuals with type 2 diabetes without macroalbuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) were included in this observational study. Recruitment spanned from January 2002 to July 2003, with prospective follow-up through January 2008. MAIN OUTCOMES AND MEASURES Chronic kidney disease was defined as new microalbuminuria or macroalbuminuria or glomerular filtration rate decline of more than 5% per year at 5.5 years of follow-up. We assessed diet using the modified Alternate Healthy Eating Index (mAHEI). The analyses were adjusted for known risk factors, and competing risk of death was considered. RESULTS After 5.5 years of follow-up, 31.7% of participants had developed CKD and 8.3% had died. Compared with participants in the least healthy tertile of mAHEI score, participants in the healthiest tertile had a lower risk of CKD (adjusted odds ratio [OR], 0.74; 95% CI, 0.64-0.84) and lower risk of mortality (OR, 0.61; 95% CI, 0.48-0.78). Participants consuming more than 3 servings of fruits per week had a lower risk of CKD compared with participants consuming these food items less frequently. Participants in the lowest tertile of total and animal protein intake had an increased risk of CKD compared with participants in the highest tertile (total protein OR, 1.16; 95% CI, 1.05-1.30). Sodium intake was not associated with CKD. Moderate alcohol intake reduced the risk of CKD (OR, 0.75; 95% CI, 0.65-0.87) and mortality (OR, 0.69; 95% CI, 0.53-0.89). CONCLUSIONS AND RELEVANCE A healthy diet and moderate intake of alcohol may decrease the incidence or progression of CKD among individuals with type 2 diabetes. Sodium intake, within a wide range, and normal protein intake are not associated with CKD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00153101.
    JAMA Internal Medicine 08/2013; 173(18). DOI:10.1001/jamainternmed.2013.9051 · 13.25 Impact Factor
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    ABSTRACT: 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 using wire myography and perivascular adipose tissue (PVAT) morphology was assessed using 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 using superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals prior to surgery. The improvement in anticontractile function following surgery was accompanied by improvements in insulin sensitivity, serum glycaemic indices, 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.
    Journal of the American College of Cardiology 05/2013; 62(2). DOI:10.1016/j.jacc.2013.04.027 · 15.34 Impact Factor
  • Anthony M Heagerty
    Hypertension 04/2013; 62(1). DOI:10.1161/HYPERTENSIONAHA.113.01359 · 7.63 Impact Factor
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    ABSTRACT: Prevention of target organ damage represents the El Dorado for clinicians who treat hypertension. Although many of the cardiovascular sequelae of chronic hypertension are due to large artery atherosclerosis, an equal number are due to small artery dysfunction. These microvascular complications include eye disease (retinopathy), kidney failure, diastolic dysfunction of the heart and small vessel brain disease leading to stroke syndromes, dementia and even depression. Examination of the retinal vasculature represents the only way to reliably derive information regarding small arteries responsible for these diverse pathologies. This review aims to summarise the rapidly accruing evidence indicating that easily observable abnormalities of retinal arteries reflect target organ damage elsewhere in the body of hypertensive patients. In tandem, we also present putative mechanisms by which hypertension and diabetes fundamentally change small artery structure and function and how these processes may lead to target organ damage.
    Current Hypertension Reports 04/2013; 15(3). DOI:10.1007/s11906-013-0347-2 · 3.90 Impact Factor
  • A H Weston · I Egner · E L Porter · Y Dong · A M Heagerty · G Edwards
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    ABSTRACT: Perivascular adipose tissue (PVAT) releases adipocyte-derived hyperpolarizing factors (ADHFs) that may partly act by opening myocyte K+ channels. The present study in rat and mouse mesenteric arteries aimed to identify the myocyte K+ channel activated by PVAT and to determine whether adiponectin contributed to the hyperpolarizing effects of PVAT. Myocyte membrane potential was recorded from de-endothelialized, non-contracted rat and mouse mesenteric arteries in the presence and absence of PVAT. The β3-adrenoceptor agonist, CL-316,243 (10 μM), generated PVAT-dependent, iberiotoxin-sensitive myocyte hyperpolarizations resulting from BKCa channel opening and which were partially blocked by L-NMMA (100 μM). Adiponectin (5 μg·mL−1) also produced iberiotoxin-sensitive hyperpolarizations in PVAT-denuded arterioles. Activation of myocyte AMP-activated protein kinase (AMPK) using 5 μM A-769662 also induced BKCa-mediated hyperpolarizations. Dorsomorphin abolished hyperpolarizations to CL-316,243, adiponectin and A-769662. In vessels from Adipo−/− mice, hyperpolarizations to CL-316,243 were absent whereas those to A-769662 and adiponectin were normal. In rat vessels, adipocyte-dependent hyperpolarizations were blocked by glibenclamide and clotrimazole but those to NS1619 (33 μM) were unaltered. Under basal, non-contracted conditions, β3-adrenoceptor stimulation of PVAT releases an ADHF, which is probably adiponectin. This activates AMPK to open myocyte BKCa channels indirectly and additionally liberates NO, which also contributes to the observed PVAT-dependent myocyte hyperpolarizations. Clotrimazole and glibenclamide each reversed hyperpolarizations to adiponectin and A-769662, suggesting the involvement of myocyte TRPM4 channels in the ADHF-induced myocyte electrical changes mediated via the opening of BKCa channels.
    British Journal of Pharmacology 03/2013; 169(7). DOI:10.1111/bph.12157 · 4.99 Impact Factor
  • Anthony M Heagerty
    The Lancet 03/2013; 381(9873). DOI:10.1016/S0140-6736(13)60639-X · 45.22 Impact Factor
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    ABSTRACT: OBJECTIVE This study aims to identify the potential mechanisms by which perivascular adipose tissue (PVAT) reduces tone in small arteries. METHODS AND RESULTS Small mesenteric arteries from wild type and BK(Ca) 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 BK(Ca) channel inhibitor or with 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 hyperpolarisation in wild type arteries was not evident in the absence or after inhibition of BK(Ca) channels. PVAT from BK(Ca) or adiponectin knockout mice failed to elicit an anticontractile response in wild type arteries. CONCLUSIONS PVAT releases adiponectin which is an anticontractile factor. Its effect on vascular tone is mediated by activation of BK(Ca) channels on vascular smooth muscle cells and adipocytes and by endothelial mechanisms.
    AJP Heart and Circulatory Physiology 01/2013; 304(6). DOI:10.1152/ajpheart.00697.2012 · 4.01 Impact Factor

Publication Stats

14k Citations
1,958.34 Total Impact Points


  • 1993–2014
    • The University of Manchester
      • • School of Biomedicine
      • • Faculty of Life Sciences
      Manchester, England, United Kingdom
  • 2007–2011
    • Central Manchester University Hospitals NHS Foundation Trust
      • Division of Medicine
      Manchester, England, United Kingdom
    • University of Milan
      Milano, Lombardy, Italy
  • 2005
    • AstraZeneca
      Tukholma, Stockholm, Sweden
  • 2003
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1986–1996
    • Aarhus University
      • Department of Pharmacology
      Aarhus, Central Jutland, Denmark
  • 1992–1994
    • University Hospital Of South Manchester NHS Foundation Trust
      Manchester, England, United Kingdom
  • 1982–1993
    • University of Leicester
      • School of Medicine
      Leiscester, England, United Kingdom
  • 1987
    • University of Vienna
      Wien, Vienna, Austria