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Lymphatic valve development

Boksik Cha, R Sathish Srinivasan
The Wnt/β-catenin signaling is an evolutionarily conserved pathway that plays a pivotal role in embryonic development and adult homeostasis. However, we have limited information about the involvement of Wnt/β-catenin signaling in the lymphatic vascular system that regulates fluid homeostasis by absorbing interstitial fluid and returning it to blood circulation. In this recent publication we report that canonical Wnt/β-catenin signaling is highly active and critical for the formation of lymphovenus valves (LVVs) and lymphatic valves (LVs)...
August 2016: BMB Reports
Silvia Martin-Almedina, Ines Martinez-Corral, Rita Holdhus, Andres Vicente, Elisavet Fotiou, Shin Lin, Kjell Petersen, Michael A Simpson, Alexander Hoischen, Christian Gilissen, Heather Jeffery, Giles Atton, Christina Karapouliou, Glen Brice, Kristiana Gordon, John W Wiseman, Marianne Wedin, Stanley G Rockson, Steve Jeffery, Peter S Mortimer, Michael P Snyder, Siren Berland, Sahar Mansour, Taija Makinen, Pia Ostergaard
Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4)...
August 1, 2016: Journal of Clinical Investigation
John D Welsh, Mark L Kahn, Daniel T Sweet
Aside from the established role for platelets in regulating hemostasis and thrombosis, recent research has revealed a discrete role for platelets in the separation of the blood and lymphatic vascular systems. Platelets are activated by interaction with lymphatic endothelial cells at the lymphovenous junction, the site in the body where the lymphatic system drains into the blood vascular system, resulting in a platelet plug that, with the lymphovenous valve, prevents blood from entering the lymphatic circulation...
September 1, 2016: Blood
Boksik Cha, Xin Geng, Md Riaj Mahamud, Jianxin Fu, Anish Mukherjee, Yeunhee Kim, Eek-Hoon Jho, Tae Hoon Kim, Mark L Kahn, Lijun Xia, J Brandon Dixon, Hong Chen, R Sathish Srinivasan
Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis...
June 15, 2016: Genes & Development
Alicia A Blancas, Liezl R Balaoing, Francisca M Acosta, K Jane Grande-Allen
Heart valvular endothelial cells (VECs) are distinct from vascular endothelial cells (ECs), but have an uncertain context within the spectrum of known endothelial phenotypes, including lymphatic ECs (LECs). Profiling the phenotypes of the heart valve surface VECs would facilitate identification of a proper seeding population for tissue-engineered valves, as well as elucidate mechanisms of valvular disease. Porcine VECs and porcine aortic ECs (AECs) were isolated from pig hearts and characterized to assess known EC and LEC markers...
2016: Cells, Tissues, Organs
Patrick L Crosswhite, Joanna J Podsiadlowska, Carol D Curtis, Siqi Gao, Lijun Xia, R Sathish Srinivasan, Courtney T Griffin
The chromatin-remodeling enzyme CHD4 maintains vascular integrity at mid-gestation; however, it is unknown whether this enzyme contributes to later blood vessel or lymphatic vessel development. Here, we addressed this issue in mice harboring a deletion of Chd4 specifically in cells that express lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), which include lymphatic endothelial cells (LECs) and liver sinusoidal endothelial cells. Chd4 mutant embryos died before birth and exhibited severe edema, blood-filled lymphatics, and liver hemorrhage...
June 1, 2016: Journal of Clinical Investigation
Rachel J Roth Flach, Chang-An Guo, Laura V Danai, Joseph C Yawe, Sharvari Gujja, Yvonne J K Edwards, Michael P Czech
The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls...
June 15, 2016: Molecular and Cellular Biology
Chloé Chong, Felix Scholkmann, Samia B Bachmann, Paola Luciani, Jean-Christophe Leroux, Michael Detmar, Steven T Proulx
Techniques to image lymphatic vessel function in either animal models or in the clinic are limited. In particular, imaging methods that can provide robust outcome measures for collecting lymphatic vessel function are sorely needed. In this study, we aimed to develop a method to visualize and quantify collecting lymphatic vessel function in mice, and to establish an in vivo system for evaluation of contractile agonists and antagonists using near-infrared fluorescence imaging. The flank collecting lymphatic vessel in mice was exposed using a surgical technique and a near-infrared tracer was infused into the inguinal lymph node...
2016: Scientific Reports
Stephanie J Munger, Xin Geng, R Sathish Srinivasan, Marlys H Witte, David L Paul, Alexander M Simon
Venous valves (VVs) are critical for unidirectional blood flow from superficial and deep veins towards the heart. Congenital valve aplasia or agenesis may, in some cases, be a direct cause of vascular disease, motivating an understanding of the molecular mechanisms underlying the development and maintenance of VVs. Three gap junction proteins (Connexins), Cx37, Cx43, and Cx47, are specifically expressed at VVs in a highly polarized fashion. VVs are absent from adult mice lacking Cx37; however it is not known if Cx37 is required for the initial formation of valves...
April 15, 2016: Developmental Biology
Gyeong Jin Kang, Tatiana Ecoiffier, Tan Truong, Don Yuen, Guangyu Li, Narae Lee, Liwei Zhang, Lu Chen
Lymphatic research signifies a field of rapid progression in recent years. Though lymphatic dysfunction has been found in a myriad of disorders, to date, few effective treatments are available for lymphatic diseases. It is therefore urgent to develop new experimental approaches and therapeutic protocols. The cornea offers an ideal site for lymphatic research due to its transparent nature, accessible location, and lymphatic-free but -inducible features. Moreover, we have recently discovered that corneal lymphatic vessels develop luminal valves as lymphangiogenesis proceeds...
2016: Scientific Reports
Tokihisa Yamasaki, Takeshi Ohdaira
In laparoscopic and thoracoscopic surgery for malignant tumors, it is often necessary to recognize intraoperative rapid diagnosis by sampling a small section of tissue that is suspected of the lymphatic or disseminated metastasis of malignant tumor cells, or of the direct invasion. However, sampling of the target tissue has to be carried out without dropping a section into the peritoneal or thoracic cavity and port-site tumor recurrence. We developed a device named the "lymph node carrier (LNC)" that is capable of instantaneously carrying a small piece of tissue out of the body after its insertion into the trocar for conventional laparoscopic surgery...
November 2015: Surgical Technology International
John T Wilson, Raoul van Loon, Wei Wang, David C Zawieja, James E Moore
The lymphatic system is vital to a proper maintenance of fluid and solute homeostasis. Collecting lymphatics are composed of actively contracting tubular vessels segmented by bulbous sinus regions that encapsulate bi-leaflet check valves. Valve resistance to forward flow strongly influences pumping performance. However, because of the sub-millimeter size of the vessels with flow rates typically <1 ml/h and pressures of a few cmH2O, resistance is difficult to measure experimentally. Using a newly defined idealized geometry, we employed an uncoupled approach where the solid leaflet deflections of the open valve were computed and lymph flow calculations were subsequently performed...
October 15, 2015: Journal of Biomechanics
Wan Qin, Utku Baran, Ruikang Wang
BACKGROUND AND OBJECTIVES: Optical microangiography (OMAG) is a noninvasive technique capable of imaging 3D microvasculature. OMAG-based optical lymphangiography has been developed for 3D visualization of lymphatic vessels without the need for exogenous contrast agents. In this study, we utilize the optical lymphangiography to investigate dynamic changes in lymphatic response within skin tissue to depilation-induced inflammation by using mouse ear as a simple tissue model. MATERIALS AND METHODS: A spectral-domain optical coherence tomography (OCT) system is used in this study to acquire volumetric images of mouse ear...
October 2015: Lasers in Surgery and Medicine
Jan Kazenwadel, Kelly L Betterman, Chan-Eng Chong, Philippa H Stokes, Young K Lee, Genevieve A Secker, Yan Agalarov, Cansaran Saygili Demir, David M Lawrence, Drew L Sutton, Sebastien P Tabruyn, Naoyuki Miura, Marjo Salminen, Tatiana V Petrova, Jacqueline M Matthews, Christopher N Hahn, Hamish S Scott, Natasha L Harvey
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations...
August 3, 2015: Journal of Clinical Investigation
Daniel T Sweet, Juan M Jiménez, Jeremy Chang, Paul R Hess, Patricia Mericko-Ishizuka, Jianxin Fu, Lijun Xia, Peter F Davies, Mark L Kahn
Fluid shear forces have established roles in blood vascular development and function, but whether such forces similarly influence the low-flow lymphatic system is unknown. It has been difficult to test the contribution of fluid forces in vivo because mechanical or genetic perturbations that alter flow often have direct effects on vessel growth. Here, we investigated the functional role of flow in lymphatic vessel development using mice deficient for the platelet-specific receptor C-type lectin-like receptor 2 (CLEC2) as blood backfills the lymphatic network and blocks lymph flow in these animals...
August 3, 2015: Journal of Clinical Investigation
Tsutomu Kume
Hemodynamic forces regulate many aspects of blood vessel disease and development, including susceptibility to atherosclerosis and remodeling of primary blood vessels into a mature vascular network. Vessels of the lymphatic circulatory system are also subjected to fluid flow-associated forces, but the molecular and cellular mechanisms by which these forces regulate the formation and maintenance of lymphatic vessels remain largely uncharacterized. This issue of the JCI includes two articles that begin to address how fluid flow influences lymphatic vessel development and function...
August 3, 2015: Journal of Clinical Investigation
Sheldon Feldman, Hannah Bansil, Jeffrey Ascherman, Robert Grant, Billie Borden, Peter Henderson, Adewuni Ojo, Bret Taback, Margaret Chen, Preya Ananthakrishnan, Amiya Vaz, Fatih Balci, Chaitanya R Divgi, David Leung, Christine Rohde
BACKGROUND: As many as 40 % of breast cancer patients undergoing axillary lymph node dissection (ALND) and radiotherapy develop lymphedema. We report our experience performing lymphatic-venous anastomosis using the lymphatic microsurgical preventive healing approach (LYMPHA) at the time of ALND. This technique was described by Boccardo, Campisi in 2009. METHODS: LYMPHA was offered to node-positive women with breast cancer requiring ALND. Afferent lymphatic vessels, identified by injection of blue dye in the ipsilateral arm, were sutured into a branch of the axillary vein distal to a competent valve...
October 2015: Annals of Surgical Oncology
John D Kanady, Stephanie J Munger, Marlys H Witte, Alexander M Simon
Connexins (Cxs), proteins that are vital for intercellular communication in vertebrates, have recently been shown to play a critical role in lymphatic development. However, our knowledge is currently limited regarding the functional relationships of Cxs with other proteins and signaling pathways. Cell culture studies have shown that Cx37 is necessary for coordinated activation of the transcription factor NFATc1, which cooperates with Foxc2 (another transcription factor) during lymphatic endothelial development...
September 1, 2015: Developmental Biology
Johanna Liebl, Siwei Zhang, Markus Moser, Yan Agalarov, Cansaran Saygili Demir, Bianca Hager, James A Bibb, Ralf H Adams, Friedemann Kiefer, Naoyuki Miura, Tatiana V Petrova, Angelika M Vollmar, Stefan Zahler
The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis...
2015: Nature Communications
Gu Zhang, John Brady, Wei-Ching Liang, Yan Wu, Mark Henkemeyer, Minhong Yan
Bidirectional signalling is regarded as a notable hallmark of the Eph-ephrin signalling system: Eph-dependent forward signalling in Eph-expressing cells and ephrin-dependent reverse signalling in Ephrin-expressing cells. The notion of ephrin-dependent reverse signalling derives from genetic experiments utilizing mice carrying mutations in the intracellular region of ephrinBs. Here we show that EphB4-dependent forward signalling regulates lymphatic valve development, a process previously thought to be regulated by ephrinB2-dependent reverse signalling...
2015: Nature Communications
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