Dr Sarah Withers
Lecturer in Biomedicine and Senior Research Scientist at Salford Royal NHS Foundation Trust
I am a Pharmacology graduate from the University of Sheffield where I received my honours degree in 2001. During my time there I met Dr Cathy Holt who worked in the Northern General Hospital and I carried out some summer research work which led to a PhD and a move to the University of Manchester. My PhD examined the role of apoptosis in restenosis (remodelling of arteries) in relation to c-Myb (a gene involved in the cell cycle). I completed my PhD in 2005 and went on to work as a post-doctoral researcher in a collaborative position between Maternal and Fetal health and Cardiovascular Sciences at Manchester.
The two year post examined the effects of internal and extravascular pressure on uterine arteries (mimicking the pressure experienced to vessels in labour/pregnancy) using a technique called pressure myography which takes segments of artery and allows physiological response to manipulation (pharmacological/physical) to be measured whilst maintained in a pressurised state, akin to vessels in vivo. This project was to determine how arteries responded to contractions during pregnancy.
I continued with my interest in cardiovascular physiology during a sustained post-doctoral position with Professor Heagerty at the Institute of Cardiovascular Sciences, University of Manchester. The overall focus of my 6 year position was to investigate the role of adipocytes (fat cells) in influencing vascular function using wire myography (vessels are mounted onto wires and their contraction measured via a transducer) and pharmacological techniques.
I developed a personal interest in the inflammatory status of adipose tissue which surrounds almost all vessels and organs to understand the role of inflammation in controlling the function of this fat tissue and its effects on small artery function. Much of my work focuses on defining the relationship of inflammation with fat cells and the pathways involved in the anticontractile effect of healthy adipose tissue and how these are affected in disease, such as obesity, cancer and dementia. My three main contributions to this area have been:
- Development of an experimental model of hypoxia, recreating the perivascular environment in obesity
- Defining a key role for immune cells in mediating the loss of anticontractile capacity of perivascular adipose tissue
- Identifying key signalling pathways involved in mediating the adiponectin-dependent anticontractile effect of perivascular adipose tissue
I teach across the Biomedical Science Programme on aspects of human physiology and pathophysiology. I also contribute to Masters teaching. I am the placement tutor for IBMS placements.
Obesity is increasing at an alarming rate and increases the risk of numerous conditions including cardiovascular disease, dementia and some cancers. There is a need to understand how this overweight state can alter function in order to identify new and effective therapies to treat obesity related disorders.
My particular interest is the inflammatory status of adipose tissue, the immune cells involved and adipo- and cytokines produced and how this intricate and complex relationship becomes dysregulated when challenged by disease. I am especially interested in how vascular function is affected. I therefore have strong collaborations with the Cardiovascular Research Group at the University of Manchester, and ongoing work in acute lymphoblastic leukaemia (Caroline Topham), Alzheimer’s disease (Gemma Lace-Costigan) and with Cardiac centre of Blackpool’s foundation trust (Nidal Bittar/Dave Greensmith). I also have a host-microbe collaboration with Drs Goodhead and Latimer and Salford Foundation Trust, in which we are investigating ventilator-associated pneumonia.
I am experienced in a number of experimental methods summarised below, but I am highly skilled in using functional techniques to examine tissue reactivity, including wire and pressure myography. These techniques are useful as they facilitate the extrapolation of physiological responses to the in vivo situation by enabling interplay between cell types, which is difficult under in vitro culture conditions.
- Pressure myography
- Wire myography
- Western blotting
- Tissue Culture-primary cell lines including porcine and murine aortic smooth muscle and endothelial cells and human saphenous vein smooth muscle cells using ex-plant and enzyme dispersal
- Apoptosis detection techniques including TUNEL, Annexin V, Hoescht Staining, DNA laddering & FACs
- Fluorescence Microscopy
- Molecular Biology, including small and large scale preparation, purification and transfection of DNA into primary cells
- Erythrocyte ghost preparation from human blood
- Optimisation of single cuvette assay and 96 well micro-array for measurement of ATPase activity
Qualifications and Memberships
Qualifications and Memberships:
- Member of the AHA (2008-Current)
- Member Physiological Society (2006-Current)
- Committee member and member of the British Society for Cardiovascular Research (2003-Current)
- Understanding Animal Research, formerly Coalition for medical progress (2008-Current)
- Honorary Lecturer at The University of Manchester
- Senior NHS Research Scientist
Withers SB, Forman R, Meza-Perez S, Sorobetea D, Sitnik K, Hopwood T, Lawrence CB, Agace WW, Else KJ, Heagerty AM, Svensson-Frej M, Cruickshank SM (2017) Eosinophils are key regulators of perivascular adipose tissue and vascular functionality. Sci Rep. 2017 Mar 17;7:44571.
Bussey CE, Withers SB, Aldous RG, Edwards G, Heagerty AM. (2016) Obesity-Related Perivascular Adipose Tissue Damage Is Reversed by Sustained Weight Loss in the Rat. Arterioscler Thromb Vasc Biol. 36(7):1377-85.
Agabiti-Rosei C, Withers SB, Greenstein AS, De Ciuceis C, Rizzoni D & Heagerty AM. (2015) Restoration of Normal Perivascular Function with Blockade of the Renin Angiotensin System in Small Arteries. Submitted to J Vasc Res 33(5):1039-45
Heerkens EH, Quinn L, Withers SB, Heagerty AM. (2014) β Integrins Mediate FAK Y397 Autophosphorylation of Resistance Arteries during Eutrophic Inward Remodeling in Hypertension. J Vasc Res. 51(4):305-14
Agabiti-Rosei C, De Ciuceis C, Rossini C, Porteri E, Rodella LF, Withers SB, Heagerty AM, Favero G , Agabiti-Rosei E, Rizzoni D, Rezzani R. (2014) Anticontractile Activity of Perivascular Fat in Obese Mice and the Effect of Long-tern Treatment with Melatonin. Journal of Hypertension 32(6):1264-74.
Withers SB, Simpson L, Fattah S, Werner ME. & Heagerty AM. (2014) cGMP dependent protein kinase (PKG) mediates the anticontractile capacity of perivascular adipose tissue. Cardiovasc Res.
Withers SB, Passi N, Williams A, de Freitas D & Heagerty AM. (2013) Restoring the anticontractile properties of adipose tissue following hypoxia using erythropoietin. J Cardiovas Dis Res. 4(3):164-9
Withers SB, Taggart M & Austin CA. (2013) Isolated Small uterine arteries from non-pregnant and term pregnant rats exhibit regulatory responses to elevations in extravascular pressure. Placenta. 34(1):82-4
Malik N, Farrell K, Withers SB, Wright E & Holt CM (2013) A novel porcine model of early left ventricular dysfunction for translational research. Res Reports Clin Cardiol. 4:1-7
Lynch FM, Withers SB, Yao Z, Werner M, Edwards G, Weston AH & Heagerty M. (2013) The response to perivascular adipose tissue is mediated by the BKCa channel and endothelial factors in mouse mesenteric arteries. AJP. 304(6):786-95
Withers SB, Agabiti-Rosei C, Livingstone DM, Little MC, Aslam R, Malik RA & Heagerty AM. (2011). Macrophage Activation is Responsible for Loss of Anticontractile Function in Inflamed Perivascular fat. ATVB. 31(4):908-13
Sonoyama K, Greenstein A, Micheletti R, Ferrari P, Schiavone A, Aghamohammadzadeh R, Withers S, Tripodi G, Ferrandi M & Heagerty A. (2011) Mutation in the β-adducin subunit causes tissue-specific damage to myogenic tone. J Hypertens;29(3):466-74
Withers SB, Taggart MJ, Baker PN & Austin CE. (2009) Responses Of Isolated Pressurized Rat Uterine Arteries to Changes in Pressure: Effects of Pre-constriction, Endothelium and Pregnancy. Placenta 30(6):529-35
Greenstein AS, Price A, Sonoyama K, Paisley A, Khavandi K, Withers SB, Shaw LM, Paniagua O, Malik RA & Heagerty AM. (2009) Eutrophic Remodeling of Small Arteries in Type 1 Diabetes Mellitus Is Enabled by Metabolic Control. A 10-Year Follow-Up Study. Hypertension 54(1):134-41
Greenstein AS, Khavandi K, Withers SB, Sonoyama KK, Clancy O, Jeziorska M, Laing I, Yates A, Pemberton P, Malik RA & Heagerty AM. (2009) Local Inflammation and Hypoxia Abolish the Protective Anticontractile Properties of Perivascular Fat in Obese Patients. Circulation 31;119(12):1661-70
Chan K, Armstrong J, Withers SB, Malik N, Cumberland D. & Gunn J & Holt C. (2007) Vascular delivery of C-myc antisense from cationically modified phosphorylcholine coated stents. Biomaterials 28(6):1218-2
Zhang Z, Cao X, Zhao X, Withers SB, Holt CM, Lewis A & Lu, J. (2006) Controlled delivery of antisense ologideoxynucleotide from cationically modified phosphorylcholine polymer films. Biomacromole 7(3):784-91
Book chapters, reviews and reports
Withers SB, Bussey CE, Saxton SN, Melrose HM, Watkins AE, Heagerty AM. Mechanisms of adiponectin-associated perivascular function in vascular disease. (2014) Arterioscler Thromb Vasc Biol. 34(8):1637-42.
Heagerty AM, Withers SB, Izzard AS, Greenstein AS & Aghamohammadzadeh R. (2013) Small Artery Structure and Function in Hypertension in Manual of Hypertension
Khavandi K, Amer H, Withers S & Afzali B. (2013) Pleiotropic effects of Vitamin D in the Oxford Textbook of Clinical Nephrology (4th Edition)
Aghamohammadzadeh R, Withers SB, Lynch FM, Greenstein AS, Malik R & Heagerty AM. (2012) Perivascular adipose tissue from human systemic and coronary vessels: The emergence of new pharmacotherapeutic target. Br J Pharmacol. 165(3):670-682
Withers S. (2011). Travel report: 10th International Symposium on Resistance Arteries Comwell Rebild Bakker, Rebild, Denmark. BSCR: The Bulletin 24(3):24-26
Farrell KA, Withers SB & Holt CM (2011). C-myb function in the vessel wall. Front Biosci. 1;3:968-77
Withers S. (2010).Travel report: 19th Annual European Society of Hypertension Milan, Italy. BSCR: The Bulletin 23(1): 17-20
Withers S, Greenstein A, Aslam K, Khavandi K, Sonoyama K, Price A, Malik RA and Heagerty AM. (2009) Investigating the effects of Aldosterone on the anti-contractile properties of perivascular fat. BSCR: The Bulletin 22(1):4-9
Asghar O, Al-Sunni A, Khavandi K, Khavandi A, Withers SB, Greenstein AS, Heagerty AM. & Malik RA. (2009). Diabetic cardiomyopathy. Clin Sci (Lond). 116(10):741-60
Khavandi K, Khavandi A, Asghar O, Greenstein AS, Withers SB, Heagerty AM & Malik RA. (2009) Diabetic cardiomyopathy-A Distinct Disease? Best Pract Res Clin Endocrinol Metab. 23(3):347-60
Khavandi K, Greenstein AS, Sonoyama KK, Withers SB, Price A, Malik RA, & Heagerty AM (2008). Myogenic tone and small artery remodelling: insight into diabetic nephropathy. Nephrol Dial Transplant. 24(2):361-9
Withers SB, Cartwright EJ & Neyses L. (2006) Sperm phenotype of mice carrying a gene deletion for the plasma membrane calcium calmodulin dependent atpase 4. Mol Cell Endocrinol 16;250(1-2):93-97