Factors responsible for venous valve development and disease

Lead Research Organisation: King's College London
Department Name: Cardiovascular

Abstract

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.

Technical Summary

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.

Publications

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Barwick TD (2014) 18F-FDG PET-CT uptake is a feature of both normal diameter and aneurysmal aortic wall and is not related to aneurysm size. in European journal of nuclear medicine and molecular imaging

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Bazigou E (2011) Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. in The Journal of clinical investigation

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Biswas JS (2013) Extra-aortic mycotic aneurysm due to group A Streptococcus after pharyngitis. in Journal of clinical microbiology

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Clough RE (2014) Pathology specific early outcome after thoracic endovascular aortic repair. in European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery

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Clough RE (2011) Endovascular treatment of acute aortic syndrome. in Journal of vascular surgery

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Evans CE (2014) Antiangiogenic therapy inhibits venous thrombus resolution. in Arteriosclerosis, thrombosis, and vascular biology

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Lyons O (2011) Endovascular management of Stanford type a dissection or intramural hematoma with a distal primary entry tear. in Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists

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Lyons O (2017) Human venous valve disease caused by mutations in and . in The Journal of experimental medicine

 
Description Change in clinical practice
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Research funded by tis award has led to a new understanding of the causes of human venous valve disease, and has elucidated cellular mechanisms underlying human venous valve failure.
 
Description Citation in Nature Medicine review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Academy of Medical Sciences Starter Grants for Clinical Lecturers
Amount £29,995 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 03/2018
 
Description BHF Centre of Excellence Overseas Exchange Award
Amount £10,000 (GBP)
Organisation Guy's and St Thomas' NHS Foundation Trust 
Sector Public
Country United Kingdom
Start 10/2013 
End 03/2014
 
Description MRC Centenary Early Careers Award
Amount £34,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2012 
End 07/2013
 
Description MRC Clinical Research Training Fellowship
Amount £267,000 (GBP)
Funding ID G1000327 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 10/2013
 
Description NIHR Clinical Lecturer
Amount £1 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2018
 
Title Knock-out model of venous valve disease 
Description Having described normal venous valve formation in mice, we have identified multiple knock-out models where venous valves do not form, and which we will use to study the role of valve failure in venous disease 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact Novel understanding of the roles of the first genes shown to be required for venous valve formation, with direct impact on patients carrying mutations in these genes who suffer from venous disease. 
 
Title NAAT 2012 reported_Improved animal model 
Description Description of normal valve development in mice & methods for wholemount confocal microscopy, enabling use of conditional knockout lines to study valve disease. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact Use in further work (publication pending) 
 
Description Valve development 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I came to Dr Makinen's lab with the idea to and methods to study venous valve formation.
Collaborator Contribution Expertise, knock-out models of disease.
Impact Bazigou.E*, Lyons.OTA*, et all. JCI. 2011 (*=joint first authors)
Start Year 2009
 
Description Valve development 
Organisation St George's University of London
Department Anatomy and Developmental Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution We carried out work to develop and utilise new methods of studying valve development in murine models and in man.
Collaborator Contribution Our collaborators have provided knowledge, experience and expertise, and worked to develop new methods.
Impact Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. Bazigou E, Lyons OT, Smith A, Venn GE, Cope C, Brown NA, Makinen T. J Clin Invest. 2011 Aug;121(8):2984-92. doi: 10.1172/JCI58050. Epub 2011 Jul 18.
Start Year 2010
 
Description Valve development 
Organisation St George's University of London
Department Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution We have contributed new methods of imaging valve disease in man.
Collaborator Contribution Our collaborators have contributed expertise, knowledge, and access to patient groups carrying genetic mutations.
Impact Expected publication 2013
Start Year 2010
 
Description Valve development 
Organisation University of Lausanne
Department Department of Biochemistry
Country Switzerland 
Sector Academic/University 
PI Contribution We have contributed methods of studying valve development.
Collaborator Contribution Our partner's have contributed knowledge, expertise and murine models.
Impact Expected publication in 2013
Start Year 2012
 
Description NAAT 2012 reported_Academic Poster Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact .
Year(s) Of Engagement Activity 2012