Molecular regulators of cardiovascular valves in development and disease

Abstract

BackgroundCardiac disease, lymphoedema, and venous reflux are associated in rare single-gene disorders but the overall molecular regulators of venous valve (VV) development and maintenance are poorly understood. Recently we compared the expression profile of murine and human VV, characterised normal VV formation in mice, and used knockout lines to show that genes required for regulating lymphatic valve development are required for VV development and maintenance. More recent developments will be presented and the genetic patterning of venous valves with respect to the genetics of human venous disease will be discussed. MethodsMurine valves were examined by light microscopy, whole-mount confocal immunofluorescence, and scanning electron microscopy in wild-type mice and genetic reporter lines. Human valves were examined by immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. Tissue-specific conditional knockout lines were used to identify roles of genes in valve formation/maintenance. FindingsMurine and human venous valves exhibit a similar structural and protein expression pattern. Several novel regulatory genes were found to be required for valve formation/maintenance. InterpretationWe have established the use of murine knockout lines in the study of venous valve disease. Venous and lymphatic valves share a common gene-expression profile and some developmental pathways, which explains the shared phenotype of lymphoedema and venous reflux seen in the clinic. Further work should be aimed at defining other genetic and environmental factors required for the development and maintenance of these complex structures, and their role in disease. FundingUK Medical Research Council.