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Dive into the research topics where Sarah Withers is active.

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Featured researches published by Sarah Withers.


Circulation | 2009

Local Inflammation and Hypoxia Abolish the Protective Anticontractile Properties of Perivascular Fat in Obese Patients

Adam Greenstein; Kaivan Khavandi; Sarah Withers; Kazuhiko Sonoyama; Olivia Clancy; Maria Jeziorska; Ian Laing; Allen P. Yates; Philip Pemberton; Rayaz A. Malik; Anthony M. Heagerty

Background— Inflammation in adipose tissue has been implicated in vascular dysfunction, but the local mechanisms by which this occurs are unknown. Methods and Results— Small arteries with and without perivascular adipose tissue were taken from subcutaneous gluteal fat biopsy samples and studied with wire myography and immunohistochemistry. We established that healthy adipose tissue around human small arteries secretes factors that influence vasodilation by increasing nitric oxide bioavailability. However, in perivascular fat from obese subjects with metabolic syndrome (waist circumference 111±2.8 versus 91.1±3.5 cm in control subjects, P<0.001; insulin sensitivity 41±5.9% versus 121±18.6% in control subjects, P<0.001), the loss of this dilator effect was accompanied by an increase in adipocyte area (1786±346 versus 673±60 &mgr;m2, P<0.01) and immunohistochemical evidence of inflammation (tumor necrosis factor receptor 1 12.4±1.1% versus 6.7±1%, P<0.001). Application of the cytokines tumor necrosis factor receptor-&agr; and interleukin-6 to perivascular fat around healthy blood vessels reduced dilator activity, resulting in the obese phenotype. These effects could be reversed with free radical scavengers or cytokine antagonists. Similarly, induction of hypoxia stimulated inflammation and resulted in loss of anticontractile capacity, which could be rescued by catalase and superoxide dismutase or cytokine antagonists. Incubation with a soluble fragment of adiponectin type 1 receptor or inhibition of nitric oxide synthase blocked the vasodilator effect of healthy perivascular adipose tissue. Conclusions— We conclude that adipocytes secrete adiponectin and provide the first functional evidence that it is a physiological modulator of local vascular tone by increasing nitric oxide bioavailability. This capacity is lost in obesity by the development of adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress.


American Journal of Physiology-heart and Circulatory Physiology | 2013

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

Fiona M Lynch; Sarah Withers; Zhihong Yao; Matthias E Werner; Gillian Edwards; Arthur H. Weston; Anthony M. Heagerty

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 Ca(2+)-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.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2011

Macrophage Activation Is Responsible for Loss of Anticontractile Function in Inflamed Perivascular Fat

Sarah Withers; Claudia Agabiti-Rosei; Daniel M. Livingstone; Matthew C. Little; Rehima Aslam; Rayaz A. Malik; Anthony M. Heagerty

Objective—The aim of this study was to determine whether macrophages dispersed throughout perivascular fat are crucial to the loss of anticontractile function when healthy adipose tissue becomes inflamed and to gain an understanding of the mechanisms involved. Methods and Results—Pharmacological studies on in vitro small arterial segments from a mouse model of inducible macrophage ablation and on wild-type animals were carried out with and without perivascular fat using 2 physiological stimuli of inflammation: aldosterone and hypoxia. Both inflammatory insults caused a similar loss of anticontractile capacity of perivascular fat and increased macrophage activation. Aldosterone receptor antagonism and free radical scavengers were able to restore this capacity and reduce macrophage activation. However, in a mouse deficient of macrophages CD11b-diptheria toxin receptor (CD11b-DTR), there was no increase in contractility of arteries following aldosterone incubation or hypoxia. Conclusion—The presence and activation of macrophages in adipose tissue is the key modulator of the increase in contractility in arteries with perivascular fat following induction of inflammation. Despite multiple factors that may be involved in bringing about the vascular consequences of obesity, the ability of eplerenone to ameliorate the inflammatory effects of both aldosterone and hypoxia may be of potential therapeutic interest.


British Journal of Pharmacology | 2012

Perivascular adipose tissue from human systemic and coronary vessels: The emergence of a new pharmacotherapeutic target

Reza Aghamohammadzadeh; Sarah Withers; Fiona M Lynch; Adam Greenstein; Rayaz A. Malik; Anthony M. Heagerty

Fat cells or adipocytes are distributed ubiquitously throughout the body and are often regarded purely as energy stores. However, recently it has become clear that these adipocytes are engine rooms producing large numbers of metabolically active substances with both endocrine and paracrine actions. White adipocytes surround almost every blood vessel in the human body and are collectively termed perivascular adipose tissue (PVAT). It is now well recognized that PVAT not only provides mechanical support for any blood vessels it invests, but also secretes vasoactive and metabolically essential cytokines known as adipokines, which regulate vascular function. The emergence of obesity as a major challenge to our healthcare systems has contributed to the growing interest in adipocyte dysfunction with a view to discovering new pharmacotherapeutic agents to help rescue compromised PVAT function. Very few PVAT studies have been carried out on human tissue. This review will discuss these and the hypotheses generated from such research, as well as highlight the most significant and clinically relevant animal studies showing the most pharmacological promise.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2014

Mechanisms of Adiponectin-Associated Perivascular Function in Vascular Disease

Sarah Withers; Charlotte Bussey; Sophie Saxton; Heather M. Melrose; Amy Watkins; Anthony M. Heagerty

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.


Nephrology Dialysis Transplantation | 2008

Myogenic tone and small artery remodelling: insight into diabetic nephropathy

Kaivan Khavandi; Adam Greenstein; Kazuhiko Sonoyama; Sarah Withers; Anna Price; Rayaz A. Malik; Anthony M. Heagerty

Diabetic nephropathy is the single most frequent cause of end-stage renal disease (ESRD) in the western world, with an estimated cost in excess of


Cardiovascular Research | 2014

cGMP-dependent protein kinase (PKG) mediates the anticontractile capacity of perivascular adipose tissue

Sarah Withers; Laura Simpson; Sharif Fattah; Matthias E. Werner; Anthony M. Heagerty

15.6 billion per annum in the United States alone [1]. In anticipation of an obesity-related diabetes epidemic, coupled with progressively growing rates of hypertension, these figures are forecast to rise exponentially. As both diabetes and renal disease are increasingly recognized as generalized vasculopathic states, there has been renewed interest in identifying potential vascular mechanisms influencing renal damage. The relationship between diabetes, hypertension and kidney disease is complex, progressive and reciprocal. In type 1 diabetes, the prevalence of microalbuminuria increases from the onset of disease, reaching 50% after 20 years [2], whilst in type 2 diabetes, it is stable at 20–25% [3]. Microalbuminuria is a powerful marker for progression to overt nephropathy [4–6] and renal function continues to decline in 30% of microalbuminuric patients with either type 1 [7] or type 2 diabetes [6]. Whilst in patients with type 1 diabetes, good glycaemic control [8] or relative youth [7] is associated with the remission of microalbuminuria, in patients with type 2 diabetes, institution of antihypertensive therapy is also important [6]. Once nephropathy is established however, ESRD occurs in 75% of individuals within 20 years [1]; at which point the cardiac mortality risk is 20-fold higher than that of the general population [9]. Thus, the stage at which diabetic renal disease is most likely to be arrested and even reversed is at the point at which microalbuminuria is detected by the clinician. The reversibility of microalbuminuria suggests an associated


Journal of Hypertension | 2014

Anticontractile activity of perivascular fat in obese mice and the effect of long-term treatment with melatonin.

Claudia Agabiti-Rosei; Carolina De Ciuceis; Claudia Rossini; Enzo Porteri; Luigi F. Rodella; Sarah Withers; Anthony M. Heagerty; Gaia Favero; Damiano Rizzoni; Rita Rezzani

AIM The aim of this study was 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. METHODS AND RESULTS 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 atrial natriuretic peptide (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. CONCLUSION 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.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2016

Obesity-Related Perivascular Adipose Tissue Damage Is Reversed by Sustained Weight Loss in the Rat

Charlotte Bussey; Sarah Withers; Robert G. Aldous; Gillian Edwards; Anthony M. Heagerty

Aims: 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. Methods and results: 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. Conclusion: Melatonin seems to exert a protective effect on arteries from both ob/ob and CLM, counteracting the adverse effect of hypoxia and iberiotoxin.


Hypertension | 2009

Eutrophic Remodeling of Small Arteries in Type 1 Diabetes Mellitus Is Enabled by Metabolic Control A 10-Year Follow-Up Study

Adam Greenstein; Anna Price; Kazuhiko Sonoyama; Angela Paisley; Kaivan Khavandi; Sarah Withers; Linda Shaw; Oscar A. Paniagua; Rayaz A. Malik; Anthony M. Heagerty

Objective— Perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists, and this is lost in obesity. A recent study reported that bariatric surgery reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been characterized after weight loss induced by caloric restriction, which is often the first line treatment for obesity. Approach and Results— Contractility studies were performed using wire myography on small mesenteric arteries with and without PVAT from control, diet-induced obese, calorie restricted and sustained weight loss rats. Changes in the PVAT environment were assessed using immunohistochemistry. PVAT from healthy animals elicited an anticontractile effect in response to norepinephrine. This was abolished in diet-induced obesity through a mechanism involving increased local tumor necrosis factor-&agr; and reduced nitric oxide bioavailability within PVAT. Sustained weight loss led to improvement in PVAT function associated with restoration of adipocyte size, reduced tumor necrosis factor-&agr;, and increased nitric oxide synthase function. This was associated with reversal of obesity-induced hypertension and normalization of plasma adipokine levels, including leptin and insulin. Conclusions— We have shown that diet-induced weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and increased nitric oxide synthase activity within PVAT. These data reveal inflammation and nitric oxide synthase, particularly endothelial nitric oxide synthase, as potential targets for the treatment of PVAT dysfunction associated with obesity and metabolic syndrome.

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Sophie Saxton

University of Manchester

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Fiona M Lynch

University of Manchester

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Cathy M. Holt

University of Manchester

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