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Title: Regulation of venous valve development and maintenance
Author: Lyons, Oliver Timothy
ISNI:       0000 0004 8499 8380
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Venous valve failure and associated venous hypertension is common in man, yet very little is known about the development and maintenance of venous valves. Existing therapies for valve failure most commonly involve removal or ablation of the vein in the superficial venous system. Little can be done to correct reflux in the deep veins. Immunofluorescence and electron microscopy were used to visualise and quantify venous valves at different stages of development in an experimental mouse model. Several proteins previously thought to be specific markers for arterial or lymphatic endothelium were found in venous endothelia and venous valves. Constitutive and conditional loss of function genetic approaches revealed how an initially homogenous population of endothelial cells acquire distinct expression patterns and behaviours, but act co-ordinately to orchestrate valve formation. The expression of several factors, previously found to be required for cardiac and/or lymphatic valve formation, was also found to be important for venous valve formation, including connexins 37, 43 and 47, integrin-α9, ephrinB2, Foxc2, and NFAT-calcineurin. Mutations in VEGFR3, FOXC2, GJC2 and GJA1 were found to be associated with structural venous valve defects in man. It has been postulated that fluid flows regulate lymphatic and venous valve development in vivo. A novel model of altered blood flow was developed, and used to show that normal blood flow is required for postnatal valve development. These data enhance our understanding of the cellular mechanisms underlying human venous valve disease caused by mutations in VEGFR3, FOXC2, GJC2 and GJA1, and suggest novel candidate genes, such as Itga9 and GJA4 for human venous valve disease. Improved knowledge of the factors regulating venous valves could lead to new treatments for valve failure, or regenerative medicine approaches to venous reflux.
Supervisor: Smith, Alberto Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available