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Lymphatic valve development

Eunson Jung, Daniel Gardner, Dongwon Choi, Eunkyung Park, Young Jin Seong, Sara Yang, Jorge Castorena-Gonzalez, Antoine Louveau, Zhao Zhou, Gene K Lee, David P Perrault, Sunju Lee, Maxwell Johnson, George Daghlian, Maria Lee, Yeo Jin Hong, Yukinari Kato, Jonathan Kipnis, Michael J Davis, Alex K Wong, Young-Kwon Hong
The lymphatic system plays a key role in tissue fluid homeostasis, immune cell trafficking, and fat absorption. We previously reported a bacterial artificial chromosome (BAC)-based lymphatic reporter mouse, where EGFP is expressed under the regulation of the Prox1 promoter. This reporter line has been widely used to conveniently visualize lymphatic vessels and other Prox1-expressing tissues such as Schlemm's canal. However, mice have a number of experimental limitations due to small body size. By comparison, laboratory rats are larger in size and more closely model the metabolic, physiological, and surgical aspects of humans...
July 17, 2017: Scientific Reports
Maximilian Nitschké, Alexander Bell, Sinem Karaman, Meelad Amouzgar, Joseph M Rutkowski, Philipp E Scherer, Kari Alitalo, Donald M McDonald
Chylous pleural effusion (chylothorax) frequently accompanies lymphatic vessel malformations and other conditions with lymphatic defects. Although retrograde flow of chyle from the thoracic duct is considered a potential mechanism underlying chylothorax in patients and mouse models, the path chyle takes to reach the thoracic cavity is unclear. Herein, we use a novel transgenic mouse model, where doxycycline-induced overexpression of vascular endothelial growth factor (VEGF)-C was driven by the adipocyte-specific promoter adiponectin (ADN), to determine how chylothorax forms...
July 3, 2017: American Journal of Pathology
Philip E Lapinski, Beth A Lubeck, Di Chen, Abbas Doosti, Scott D Zawieja, Michael J Davis, Philip D King
Capillary malformation-arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) disorder that is caused by inherited inactivating mutations of the RASA1 gene, which encodes p120 RasGAP (RASA1), a negative regulator of the Ras small GTP-binding protein. How RASA1 mutations lead to the LV leakage defects that occur in CM-AVM is not understood. Here, we report that disruption of the Rasa1 gene in adult mice resulted in loss of LV endothelial cells (LECs) specifically from the leaflets of intraluminal valves in collecting LVs...
June 30, 2017: Journal of Clinical Investigation
Shi-Min Yuan
Congenital pulmonary lymphangiectasia (CPL) is a rare but fatal disease, usually having an onset from the first few hours to days after birth. Inconsistent nomenclatures were used for CPL in the past decades. Patients often present with intractable respiratory failure, hydrops fetalis and even sudden death. The etiologies of CPL remain unclear. Previous hypotheses suggested that CPL might be caused by conditions preventing normal regression of the lymphatics after the 18th-20th week of gestation. Up-to-date biological studies on lymphatic development, lymphatic valve formation and occurrence of hydrops fetalis revealed possible causative relations with mutations of genes of the vascular endothelial growth factor receptor (VEGFR), RAS/MAPK, PI3K/AKT and NF-κB signaling pathways...
March 4, 2017: Journal of Perinatal Medicine
V Núñez Cerezo, M I Romo Muñoz, J Jiménez Gómez, P Triana Junco, A Sánchez Galán, G Chocarro Amatriain, J C López Gutiérrez
OBJECTIVES: To analyze and describe the association between the development of venous aneurysms of the mayor vessels in patients with lymphatic malformations. MATERIAL AND METHODS: Retrospective review of patients diagnosed with both VA and LM from 1993 to 2014 and a descriptive analysis of clinical course was performed. RESULTS: We found 6 patients, 50% females, who had LM and VA confirmed with imaging techniques. All were diagnosed between 20 weeks- 12 years of age...
April 10, 2016: Cirugía Pediátrica: Organo Oficial de la Sociedad Española de Cirugía Pediátrica
Stephanie J Munger, Michael J Davis, Alexander M Simon
Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development...
January 15, 2017: Developmental Biology
Gyeong Jin Kang, Tan Truong, Eric Huang, Valerie Su, Shaokui Ge, Lu Chen
Purpose: The lymphatic pathway mediates transplant rejection. We recently reported that lymphatic vessels develop luminal valves in the cornea during lymphangiogenesis, and these valves express integrin alpha 9 (Itga-9) and play a critical role in directing lymph flow. In this study, we used an allogeneic corneal transplantation model to investigate whether Itga-9 blockade could suppress valvulogenesis after transplantation, and how this effect would influence the outcomes of the transplants...
November 1, 2016: Investigative Ophthalmology & Visual Science
Yingdi Wang, Nicolas Baeyens, Federico Corti, Keiichiro Tanaka, Jennifer S Fang, Jiasheng Zhang, Yu Jin, Brian Coon, Karen K Hirschi, Martin A Schwartz, Michael Simons
The role of fluid shear stress in vasculature development and remodeling is well appreciated. However, the mechanisms regulating these effects remain elusive. We show that abnormal flow sensing in lymphatic endothelial cells (LECs) caused by Sdc4 or Pecam1 deletion in mice results in impaired lymphatic vessel remodeling, including abnormal valve morphogenesis. Ablation of either gene leads to the formation of irregular, enlarged and excessively branched lymphatic vessels. In both cases, lymphatic valve-forming endothelial cells are randomly oriented, resulting in the formation of abnormal valves...
December 1, 2016: 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...
March 10, 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...
January 20, 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
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