Factors responsible for venous valve development and disease

Varicose veins are a very common condition in which malfunction of the valves within the veins leads to high blood pressure in the leg veins. This damages the skin and can cause repeated leg ulceration. We know very little about how the valves in veins grow, and this makes it difficult to tell exactly what problems with the valves could cause varicose veins - it could be a problem with the vein wall or with the valves themselves. This project will tell us not only how the valves in veins develop, but also what genes control the process and their interaction with factors such as blood flow. We will study the structure of the venous valves in people who have a faulty gene that causes varicose veins. We hope to find out something about the causes of varicose veins. This understanding could allow us to develop better treatments such as replacements for faulty venous valves, or even prevent them from occurring in the first place.

Treatment of venous disease consumes approximately 2% of the NHS budget. Varicose veins and their complications affect a large proportion of the population, and in some people produce clinical complications including venous hypertension and chronic ulceration. This may be caused by failure of vein valves (VV) to function normally, which either results from an intrinsic valvular defect or is secondary to a dilatation of the vein wall. There are almost no data available that describe the mechanisms that give rise to VV formation other than basic histological studies. An association has, however, recently been found between varicose veins in the general population and the gene encoding the transcription factor Foxc2 which is mutated in those patients with lymphoedema distichiasis (a form of primary lymphatic dysfunction). In addition, it has long been thought that flow may affect the development of valves in the heart, and there is circumstantial evidence to suspect this also occurs in the development of venous and lymphatic valves.

We hypothesise that:
1 the mechanisms that regulate the development of venous and lymphatic valves are similar;
2. shear force is an important regulator of venous valve development
3. regulation of venous valve formation is disrupted in patients with mutations in the gene encoding FOXC2 (and other candidates)

We propose to:
1) use reporter and imaging techniques to describe normal VV morphogenesis and define the valve phenotype when pathways (which are known to be important in lymphatic valve development) are disrupted;
2) develop a dynamic computational model of flow through the developing valve to help determine the importance of flow in normal valve development;
3) characterise the defect in venous valves in patients with Foxc2 and other mutations.

Scientific and medical opportunities
This project will provide the first description of normal murine VV morphogenesis including the role played by several candidate key genes. It will also extend our understanding of the role of some candidate genes in inherited human venous valve failure. This will provide the basis for human genetic studies of the cause of heritable valvular abnormalities such as primary valvular agenesis and varicose veins.