Vascular function and pathophysiology

A particular strength within the ICMR is our focus on the physiology and pathophysiology of vascular function, and its modulation by dietary components.

Vascular dysfunction is recognised to be a central pathological feature of cardiovascular disease involving dysregulation of numerous cell types in the vascular wall. Dysfunction of the endothelial cell layer which lines the blood vessels is considered an initiating event in atherogenesis, with damage to its barrier function, increased chemokine secretion and adhesion molecule expression, leading to leukocyte recruitment into the subendothelial space. In the intimal area, macrophage lipid accumulation and secretion of pro-inflammatory mediators, together with vascular smooth muscle cell (VSMC) proliferation and their intimal infiltration, accelerate the atherogenic process. Vascular reactivity/tone, which serves as a marker for general vascular dysfunction, is mediated by VSMC and in large part is influenced by a range of vasoconstrictors and vasodilators derived from endothelial cells. In recent years, the prognostic ability of vascular reactivity of both the coronary and peripheral arteries in predicting future coronary events has been widely recognised.

Within the ICMR we employ numerous models to study vascular function, including trials in human volunteers. We have an extensive range of techniques to non-invasively study human vascular 'health' and reactivity such as flow mediated dilation (FMD), laser doppler iontophoresis (LDI), pulse wave analysis (PWA), pulse wave velocity (PWV) and contrast angiography.

Diet, and in particular dietary fat composition, together with insulin sensitivity and common gene variants are thought to have a significant impact on vascular function and reactivity. Ongoing research programmes within the ICMR are examining the individual and interactive influence of these factors on vascular 'health' and investigating underlying molecular mechanisms.

We also have research interests in understanding the mechanisms involved in the development of in-stent stenosis in stented vessels following balloon angioplasty. It is known that this response to injury is largely driven by excessive VSMC proliferation and our interest in cell cycle regulation of cardiovascular cells is seeking to identify novel mechanisms through which we might inhibit the excessive growth of VSMCs and reduce the incidence of in-stent stenosis.

We are also interested in the migration of endothelial cells, a process that is important for both the formation of new blood vessels and the repair of damaged vessels. Cell migration is an extremely complex and tightly regulated process requiring the co-ordinated activity of hundreds of proteins. During cell migration the leading edge of a cell demonstrates membrane protrusion, adhesion site formation and the generation of force which pulls the cell forward. The protrusion of the plasma membrane at the leading edge is driven by extensive actin polymerisation and leads to the formation of the lamellipodium, often accompanied by membrane ruffling. Formation of adhesion complexes attaches the lamellipodium to the surface and allows the cell to generate traction. These adhesion complexes form only transient attachments in actively migrating cells and therefore require rapid assembly and disassembly. Our research aims to understand the molecular mechanisms underlying this complex process.