Highlighted Paper: Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice.

The Lymphatic Development Laboratory, headed by Taija Makinen published this paper in the Journal of Clinical Investigation.

The clinical problems that arise from venous valve incompetence, including chronic venous disease and venous hypertension, highlight the importance of valves in assuring unidirectional flow and efficient return of blood, especially from the lower extremities. The mechanisms that regulate venous valve development have, however, not been described. In this paper, we have developed methods to visualise and genetically target venous valves in mice.

Scanning electron microscopy image of resin cast of a vein showing three valves.

Using high-resolution microscopy analysis and genetic mouse models we show that the morphogenetic process of valve development occurs similarly in veins to what we have previously described in lymphatic vessels. Unexpectedly, we found that venous valve development involve a key regulator of arterial identity, Ephrin-B2. Intriguingly, developing and mature venous valves also express a repertoire of proteins, such as Prox1, VEGFR-3 and Integrin-alpha9, that have previously been characterised as specific and critical regulators of lymphangiogenesis. Using genetic mouse mutants we further demonstrate the requirement of Ephrin-B2 and Integrin-alpha9 signalling for the development and maintenance of venous and lymphatic valves.

In summary, our study identifies the first molecular regulators of venous valves and highlights involvement of common morphogenetic processes and signalling pathways in controlling valve formation in veins and lymphatic vessels. In addition, the unique molecular identity of venous valve endothelial cells that closely resembles lymphatic (valve) endothelia suggests plasticity in the ability of a terminally differentiated endothelial cell to take on a different phenotypic identity and thus challenges the common view that endothelial cells in different types of vessels represent distinct terminally differentiated cell lineages whose identity is strictly genetically determined.