Interplay of Mechanotransduction, FOXC2, Connexins, and Calcineurin Signaling in Lymphatic Valve Formation
The directional flow of lymph is maintained by hundreds of intraluminal lymphatic valves. Lymphatic valves are crucial to prevent lymphedema, accumulation of fluid in the tissues, and to ensure immune surveillance; yet, the mechanisms of valve formation a
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Interplay of Mechanotransduction, FOXC2, Connexins, and Calcineurin Signaling in Lymphatic Valve Formation Ame´lie Sabine and Tatiana V. Petrova
Abstract The directional flow of lymph is maintained by hundreds of intraluminal lymphatic valves. Lymphatic valves are crucial to prevent lymphedema, accumulation of fluid in the tissues, and to ensure immune surveillance; yet, the mechanisms of valve formation are only beginning to be elucidated. In this chapter, we will discuss the main steps of lymphatic valve morphogenesis, the important role of mechanotransduction in this process, and the genetic program regulated by the transcription factor Foxc2, which is indispensable for all steps of valve development. Failure to form mature collecting lymphatic vessels and valves causes the majority of postsurgical lymphedema, e.g., in breast cancer patients. Therefore, this knowledge will be useful for diagnostics and development of better treatments of secondary lymphedema.
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Introduction
Lymphatic vessels contain two distinct functional compartments: lymphatic capillaries and collecting vessels. The main function of lymphatic capillaries is the uptake of interstitial fluid. They also serve as a principal point of entry for antigen-presenting cells, which is important for triggering immune responses. A. Sabine Department of Oncology, CHUV-UNIL, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland T.V. Petrova (*) Department of Oncology, CHUV-UNIL, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland E´cole Polytechnique Fe´de´rale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), Lausanne, Switzerland e-mail: [email protected] F. Kiefer and S. Schulte-Merker (eds.), Developmental Aspects of the Lymphatic Vascular System, Advances in Anatomy, Embryology and Cell Biology 214, DOI 10.1007/978-3-7091-1646-3_6, © Springer-Verlag Wien 2014
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A. Sabine and T.V. Petrova
Collecting lymphatic vessels receive the lymph from capillaries and transport it towards lymph nodes. Efficient transport of lymph is enabled through several mechanisms: in capillaries overlapping endothelial cell borders form flaps, which prevent lymph exit immediately after the uptake; contraction of smooth muscle cells and surrounding tissues, such as skeletal muscle, propels the lymph in collecting vessels; and intraluminal valves prevent lymph reflux. The exact number of lymphatic valves in humans or mice is not known. Adult mouse mesenteric lymphatic vessels have at least 500–800 valves (E. Bovay and A. Sabine, unpublished observation), highlighting the importance of this system for normal lymph transport. In this chapter, we will review the molecular mechanisms underlying formation of lymphatic valves with an emphasis on the role of forkhead transcription factor Foxc2, which acts as an essential regulator of valve development. In addition, current knowledge of human pathologies linked to dysfunctional or
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