Atherothrombosis


What

Approximately a quarter of a million patients suffer a heart attack (or myocardial infarction, MI) in the UK each year, and around 120,000 of these die.

MI is caused by the formation of a blood clot (thrombosis) superimposed on a ruptured or surface-eroded coronary atherosclerotic plaque. This process is called atherothrombosis (illustrated in the image above).

Identifying the causes and devising new treatments for these ‘vulnerable’ plaques are internationally recognised priorities, and are at the heart of our research.

We have made major contributions to understanding how arterial smooth muscle cells behave and how these behaviours contribute to atherogenesis and to vein graft failure. Our research has also greatly increased our understanding of matrix degrading metalloproteinases in weakening the plaque extracellular matrix and the pathways that regulate their production.

endothelial cells regrowing in injured arterySimilarly, we conduct world-leading research on the molecular biology of vascular smooth muscle cells that repair such injuries, and on the causes of endothelial dysfunction, which predisposes patients - particularly those with diabetes - to MI. (Image right shows endothelial cells regrowing into an injured artery.)

Finally, we have made groundbreaking discoveries in the area of platelet biology, as these platelet producing blood cells (see image top right) are at the centre of the developing thrombus that blocks the vessel.  We have identified a number of genes that regulate these cells, and have identified mutations in some of these genes that underlie platelet dysfunction in man. 

Where

Research is conducted mostly by people in the School of School of Physiology and Pharmacology, and the School of Clinical Sciences.

How

Characteristic methods and techniques routinely used in this area of research include:

  • Confocal imaging
  • Total Internal Reflection Fluorescent (TIRF) microscopy
  • Electron microscopy
  • Mass spectrometry and proteomics
  • Protein biochemistry e.g. immunocytochemistry, cellular fractionation and western blotting
  • Primary cell culture of rat, mouse and human smooth muscle cells
  • Culture of primary macrophages
  • Methods used in cell culture including histology, apoptosis assays, immunohistochemistry, proliferation and migration assays
  • In vitro models of intimal thickening: human saphenous vein organ cultures and mouse carotid artery ligations
  • Using mouse model systems including gene knockouts, and models of atherosclerosis and aneurysm formation
  • Resin cast of mouse vasculatureMethods for study and assessment of mice, e.g. genotyping, vascular surgery, circulatory manipulation, dietary modification, stress studies, measuring blood pressure, atherosclerosis, and arterial morphology (image shows a resin cast of mouse blood vessels)

Highlights

Current projects include:

  • Role of the cell-adhesion proteins cadherins and signaling proteins Wnts in atherosclerosis and aneurysms e.g. via modulation of smooth muscle cell, endothelial cell and macrophage behaviour
  • Studying the potential of soluble cadherins for treatment of cardiovascular disease
  • The roles of vitamin D and of blood flow dynamics in atherosclerosis
  • Platelet secretion and function, eg the roles of protein kinase C, and of the motor protein myosin Va
  • Regulation of platelet P2Y receptor traffic and function, e.g. modulation by NHERF proteins
  • The roles of transglutaminases in arterial and myocardial pathophysiology and the role of C-reactive protein in arterial injury
  • Elucidating statin mechanisms of action

More information

Further details on research into atherothrombosis can be found at:

Bristol platelet group

Genotyping & Phenotyping of Platelets