... understanding life in molecular detail

Dr Vas Ponnambalam

Receptor-ligand structure and function; Receptor tyrosine kinases; Scavenger receptors; Blood vessels; Endothelium; Atherosclerosis; Cancer


The vascular system is made of different cell types that cooperate to regulate blood vessel formation and vascular physiology. The endothelial cell monolayer that lines all blood vessels plays key roles in diverse phenomena including new blood vessel sprouting (angiogenesis), blood pressure and wound healing. My laboratory is investigating how diverse substances which circulate in the blood and extracellular fluids such as growth factors or lipid particles regulate intracellular signalling and vascular physiology. Understanding such phenomena is helps to also devise new therapeutics and diagnostics for vascular disease therapy. Situations for clinical intervention include arterial repair and regeneration after heart attacks or strokes, diagnosing early events in atherosclerosis, and blocking solid tumour growth and metastasis.

Current major projects include:
  • VEGFR2(KDR) receptor tyrosine kinase activity in endothelial function
  • VEGFR1(Flt-1) receptor tyrosine kinase regulating endothelial function
  • LOX-1 endocytosis via a clathrin-independent pathway
  • LOX-1 as biomarker for cardiovascular disease

Areas from which our research benefits from collaborations within Leeds include the Endothelial Cell Biology Unit which comprises the groups of Ponnambalam, Homer-Vanniasinkam and Walker with an ethos of basic science translation into medicine. Cardiovascular research and translational research is further fostered by links to groups within the MultiDisciplinary Cardiovascular Research Centre (MCRC) and Biomedical Health Research Centre. We are carrying out structure-function studies through collaborations with the Astbury Centre for Structural Molecular Biology. We are using physical sciences input to discover new therapeutics and ways of investigating biological function through collaborations with the School of Chemistry and School of Mathematics.

1) VEGFR-VEGF regulation of endothelial function - Vascular endothelial growth factor A (VEGF-A) binds receptor tyrosine kinases (VEGFR1 and VEGFR2) on the surface of endothelial cells to activate intracellular signalling, vasodilation (reduced blood pressure), vasculogenesis, angiogenesis and wound healing. A key feature of endothelial cells is their ability to mediate angiogenesis i.e. the sprouting of new blood vessels from pre-existing blood vessels. Understanding how VEGF-A regulates VEGFR signalling will provide knowledge for better pro-angiogenic (to repair damaged blood vessels after heart attacks) or anti-angiogenic (to block blood vessel growth during cancer metastasis) therapies.

2) Scavenger receptor regulation of vascular function & atherosclerosis - The human lectin-like LOX-1 scavenger receptor promotes atherosclerotic plaque initiation and progression. Genetic mutations or polymorphisms in the LOX-1 gene are linked to increased incidence of vascular disease including heart attacks. One idea is that ‘knocking out’ or inhibiting LOX-1 function could be beneficial for preventing atherosclerosis leading to plaque initiation and progression in arteries. LOX-1 is expressed on different vascular tissues including the endothelium, vascular smooth muscle and leukocytes (monocytes and macrophages). Understanding how LOX-1 regulates cell function and vascular physiology will enable us to target it for therapy.

Our work also benefits from collaboration with basic scientists and clinicians within Leeds. Notably, our clinical collaborators include cardiologists Dr Stephen Wheatcroft, Professor Mark Kearney (Division of Cardiovascular Research & Diabetes, Faculty of Medicine & Health) and vascular surgeon Professor Shervanthi Homer-Vanniasinkam (Leeds Vascular Institute, Leeds General Infirmary). We have collaborations with Professor Carmen Molina-Paris, Dr Grant Lythe (School of Mathematics), Professor Colin Fishwick and Dr Bruce Turnbull (School of Chemistry). Within the Faculty of Biological Sciences, we have ongoing collaborations with Dr Darren Tomlinson, Dr John Walker, Dr Anastasia Zhuravleva (School of Molecular & Cellular Biology), Dr Michael Harrison, Dr Stephen Muench and Prof. Paul Millner (School of Biomedical Sciences).

Our current work is funded by the British Heart Foundation, Heart Research UK, The Leverhulme Trust, AstraZeneca, Circulation Foundation & Brunei Darussalam government. Previous funding agencies for projects and equipment were from the Medical Research Council, The Wellcome Trust, BBSRC, European Union, Yorkshire Cancer Research, Pfizer Global Inc., White Rose Network and Yorkshire Enterprise Fellowship scheme.

Detailed research programme                  Close ▲

Selected Publications

  1. Bruns AF, Yuldasheva N, Latham AM, Caroline Pellet-Many C, Bao L, Frankel P, Stephen SL, Howell GJ, Wheatcroft SB, Kearney MT, Zachary IC, Ponnambalam S (2012) A heat-shock protein axis regulates VEGFR2 proteolysis, blood vessel development and repair. PLoS One 7:e48539. doi:10.1371/journal.pone.0048539.

  2. Kankanala J, Latham AM, Johnson AP, Homer-Vanniasinkam S, Fishwick CWG, Ponnambalam S (2012) A combinatorial in silico and cellular approach to identify a new class of compounds that target VEGFR2 receptor tyrosine kinase activity and angiogenesis. Br J Pharmacology 166:737-745.

  3. Bruns AF, Herbert SP, Odell AF, Jopling HM, Hooper NM, Zachary IC, Walker JH, Ponnambalam S (2010) Ligand-stimulated VEGFR2 signaling is regulated by co-ordinated trafficking and proteolysis. Traffic 11:161-174.

  4. Murphy JE, Vohra RS, Dunn S, Holloway Z, Monaco AP, Homer-Vanniasinkam S, Walker JH, Ponnambalam S (2008) Oxidized low-density lipoprotein internalization by the LOX-1 scavenger receptor is dependent on a novel cytoplasmic motif and regulated by dynamin-2. J Cell Sci 121:2136-2147.