scholarly journals REVIEW OF THE FUNCTION OF SEMA3A IN LYMPHATIC VESSEL MATURATION AND ITS POTENTIAL AS A CANDIDATE GENE FOR LYMPHEDEMA: ANALYSIS OF THREE FAMILIES WITH RARE CAUSATIVE VARIANTS

Lymphology ◽  
2020 ◽  
Vol 53 (2) ◽  
Author(s):  
M Ricci ◽  
C Daolio ◽  
B Amato ◽  
S Kenanoglu ◽  
D Veselenyiova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Candidate Gene ◽  
Protein Interactions ◽  
Lymphatic Vessel ◽  
Lymphatic System ◽  
Lymphatic Vessels ◽  
Wild Type ◽  
Neuropilin 1 ◽  
Vessel Maturation ◽  
Vessel Development

SEMA3A is a semaphorin involved in cell signaling with PlexinA1 and Neuropilin-1 (NRP1) receptors and it is responsible for recruiting dendritic cells into lymphatics. Mutations in the SEMA3A gene result in abnormalities in lymphatic vessel development and maturation. We investigated the association of SEMA3A variants detected in lymphedema patients with lymphatic maturation and lymphatic system malfunction. First, we used NGS technology to sequence the SEMA3A gene in 235 lymphedema patients who carry wild type alleles for known lymphedema genes. We detected three different missense variants in three families. Bioinformatic results showed that some protein interactions could be altered by these variants. Other unaffected family members of the probands also reported different episodes of subclinical edema. We then evaluated the importance of the SEMA3A gene in the formation and maturation of lymphatic vessels. Our results determined that SEMA3A variants segregate in families with lymphatic system malformations and recommend the inclusion of SEMA3A in the gene panel for testing of patients with lymphedema.

scholarly journals S1P-S1PR1 activity controls VEGF-A signaling during lymphatic vessel development

2019 ◽  
Author(s):  
AM Golding-Ochsenbein ◽  
S Vidal ◽  
B Wilmering Wetter ◽  
C Guibourdenche ◽  
C Beerli ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Signaling Crosstalk ◽  
Balanced Growth ◽  
Sphingosine 1 Phosphate ◽  
Genetic Deletion ◽  
Vessel Development ◽  
Perinuclear Area

AbstractSphingosine-1-phosphate (S1P), a lipid signaling molecule produced by endothelial cells, is required for development and homeostasis of blood vessels. However, its role during lymphatic vessel development is unclear. We show in murine newborns that pharmacologically enhanced S1P signaling increases VEGF-A-dependent LEC proliferation. In contrast, S1PR1 inhibition, mediated by the antagonist NIBR0213 or LEC-specific genetic deletion of S1pr1, promotes filopodia formation and vessel branching, independent of VEGF-A. To investigate the S1P and VEGF-A signaling crosstalk observed in vivo, we used LECs cultured in vitro. We demonstrate that S1P activates endogenous S1PR1 in a constitutive, autocrine manner. Importantly, S1P-S1PR1 activity was required for VEGF-A-induced LEC proliferation and strongly supported ERK1/2 activation and VEGFR-2 trafficking to the perinuclear area. In conclusion, S1P-S1PR1 signaling promotes VEGF-A-dependent LEC proliferation and limits migratory and filopodia-forming responses. Hence, S1P-S1PR1 signaling is required for balanced growth factor-induced lymphangiogenesis and correctly patterned lymphatic vessels during postnatal development.

scholarly journals SVEP1 IS IMPORTANT FOR MORPHOGENESIS OF LYMPHATIC SYSTEM: POSSIBLE IMPLICATIONS IN LYMPHEDEMA

Lymphology ◽  
2021 ◽  
Vol 54 (1) ◽  
Author(s):  
S. Michelini ◽  
B. Amato ◽  
M. Ricci ◽  
R. Serrani ◽  
D. Veselenyiova ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Protein Interactions ◽  
Lymphatic System ◽  
Review Of The Literature ◽  
Single Nucleotide Variants ◽  
Lymphatic Malformations ◽  
Single Nucleotide ◽  
Three Samples ◽  
Knockout Animals ◽  
Mosaic Protein

SVEP1, also known as Polydom, is a large extracellular mosaic protein with functions in protein interactions and adhesion. Since Svep1 knockout animals show severe edema and lymphatic system malformations, the aim of this study is to evaluate the presence of SVEP1 variants in patients with lymphedema. We analyzed DNA from 246 lymphedema patients for variants in known lymphedema genes, 235 of whom tested negative and underwent a second testing for new candidate genes, including SVEP1, as reported here. We found three samples with rare heterozygous missense single-nucleotide variants in the SVEP1 gene. In one family, healthy members were found to carry the same variants and reported some subclinical edema. Based on our findings and a review of the literature, we propose SVEP1 as a candidate gene that should be sequenced in patients with lymphatic malformations, with or without lymphedema, in order to investigate and add evidence on its possible involvement in the development of lymphedema.

Abstract 15945: Cdc42 is Required for Lymphatic Branching, Maturation and Valve Formation During Development

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yixin Jin ◽  
Yang Liu ◽  
Hailin Chen ◽  
Rui Wang ◽  
Hongjiang Si ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Cell Polarization ◽  
Embryonic Lethality ◽  
Vascular Endothelial ◽  
Cellular Functions ◽  
Proliferation And Differentiation ◽  
Vessel Maturation ◽  
Valve Formation

Cdc42 is a Ras-related GTPase that plays an important role in regulation of actin cytoskeletal architecture. Blocking the ability of Cdc42 to activate its effectors has been shown to inhibit a range of cellular functions including cell polarization, migration, proliferation and differentiation. Consistent with its critical roles in vitro, the inactivation of Cdc42 in mice resulted in embryonic lethality before E6.5. The early embryonic lethal phenotype of Cdc42-null mice has made it not useful for studies on the interesting questions of the roles and mechanisms of Cdc42 in the vascular development. To overcome this problem, we have generated an endothelial cell (EC) specific Cdc42 knockout mouse line by crossing Cdc42/flox mice with vascular endothelial cadherin Cre mice. Our results have demonstrated that the deletion of Cdc42 in ECs resulted in embryonic lethality with severe edema. Whole mount immunofluorescence staining showed mesentery collecting lymphatic vessel maturation and valve formation defects. Interestingly, lymphangiogenesis in the intestine wall was totally disrupted in Cdc42 EC knockout embryos. Moreover, we analyzed the role of Cdc42 in lymphatic vessel formation in the skin. We found that Cdc42 is required for tip cells filopodia formation and the deletion of Cdc42 in endothelial cells impaired lymphatic vessel sprouting, branching and the mutant lymphatic vessels displayed blunt-ended, bulbous lymphatic. We also noted that the size of lymphatic lumen was significantly increased. Taken together, our data suggested that Cdc42 plays an essential role in lymphatic branching, maturation and valve formation during development.

scholarly journals Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation

Blood ◽  
2016 ◽  
Vol 128 (9) ◽  
pp. 1169-1173 ◽  
Author(s):  
John D. Welsh ◽  
Mark L. Kahn ◽  
Daniel T. Sweet
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Lymph Flow ◽  
The Body ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Circulation ◽  
Vessel Maturation

Abstract 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. This process, known as “lymphovenous hemostasis,” is mediated by activation of platelet CLEC-2 receptors by the transmembrane ligand podoplanin expressed by lymphatic endothelial cells. Lymphovenous hemostasis is required for normal lymph flow, and mice deficient in lymphovenous hemostasis exhibit lymphedema and sometimes chylothorax phenotypes indicative of lymphatic insufficiency. Unexpectedly, the loss of lymph flow in these mice causes defects in maturation of collecting lymphatic vessels and lymphatic valve formation, uncovering an important role for fluid flow in driving endothelial cell signaling during development of collecting lymphatics. This article summarizes the current understanding of lymphovenous hemostasis and its effect on lymphatic vessel maturation and synthesizes the outstanding questions in the field, with relationship to human disease.

scholarly journals Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis

2021 ◽  
pp. 153537022110210
Author(s):  
Chu-An Wang ◽  
Shaw-Jenq Tsai
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Lymphatic Metastasis ◽  
Lymphatic Vessel ◽  
Cancer Metastasis ◽  
Lymphatic System ◽  
Lymphatic Vessels ◽  
Extracellular Vesicle ◽  
Tissue Fluid ◽  
Vessel Infiltration

Metastasis is not only one of the hallmarks of cancer but, unfortunately, it also is the most accurate biomarker for poor prognosis. Cancer cells metastasize through two different but eventually merged routes, the vasculature and lymphatic systems. The processes of cancer metastasis through blood vessel have been extensively studied and are well documented in the literature. In contrast, metastasis through the lymphatic system is less studied. Most people believe that cancer cells metastasize through lymphatic vessel are passive because the lymphatic system is thought to be a sewage draining system that collects whatever appears in the tissue fluid. It was recently found that cancer cells disseminated from lymphatic vessels are protected from being destroyed by our body’s defense system. Furthermore, some cancer cells or cancer-associated immune cells secrete lymphangiogenic factors to recruit lymphatic vessel infiltration to the tumor region, a process known as lymphangiogenesis. To ensure the efficiency of lymphangiogenesis, the lymphangiogenic mediators are carried or packed by nanometer-sized particles named extracellular vesicles. Extracellular vesicles are lipid bilayer particles released from eventually every single cell, including bacterium, with diameters ranging from 30 nm (exosome) to several micrometers (apoptotic body). Components carried by extracellular vesicles include but are not limited to DNA, RNA, protein, fatty acid, and other metabolites. Recent studies suggest that cancer cells not only secrete more extracellular vesicles but also upload critical mediators required for lymphatic metastasis onto extracellular vesicles. This review will summarize recent advances in cancer lymphatic metastasis and how cancer cells regulate this process via extracellular vesicle-dependent lymphangiogenesis.

scholarly journals Design of an Auxiliary Artificial Lymphatic Vessel in Treatment of Secondary Lymphedema Due to Breast Cancer

Healthcare ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 68
Author(s):  
Gabriela Durán-Aguilar ◽  
Alberto Rossa-Sierra ◽  
Rita Q. Fuentes-Aguilar
Keyword(s):  
Breast Cancer ◽  
Lymphatic Vessel ◽  
Lymphatic System ◽  
Breast Cancer Incidence ◽  
Lymphatic Vessels ◽  
The United States ◽  
Fluid Simulation ◽  
Secondary Lymphedema ◽  
Flow Through ◽  
Survival Patterns

Breast cancer is the most common malignant tumor that affects women in the United States, Europe, and Mexico. As an adverse effect when performing treatments for this condition, secondary lymphedema associated with breast cancer occurs in some cases. This complication occurs due to the interruption of lymphatic flow in the upper extremities in conjunction with other factors such as radiation, sedentary lifestyle, removal of lymph nodes, damage to lymphatic vessels, and others. This article reviews breast cancer incidence, mortality, and survival patterns, confirming that, specifically, lymphedema has high health, social, and economic impacts. Research demonstrates that it fundamentally affects women at an early age. In approximately a third of the cases, it becomes a chronic disease. Therefore, physical therapy is essential for a better quality of life in patients who survive this disease. Surgeries and manual and pharmacological treatments are the current procedures done to reduce to reduce the alterations suffered by patients with lymphedema; however, the success of the treatments depends on each patient’s characteristics. To face this problem, the design of a lymphatic vessel has been proposed to assist the mechanical failure of the damaged lymphatic system. In this work, the design methodology used for the blueprint of the lymphatic vessel is presented, as well as the computer analysis of fluid simulation and the selection of the proposed material, resulting in the production of a micrometric design. In the future, it is expected that a surgeon will be able to implant the design of the vessel to restore lymph flow through the lymphatic system, thus helping to combat lymphedema.

Initial Steps Toward Development of a Lumped-Parameter Model of the Lymphatic Network

2013 ◽  
Author(s):  
Samira Jamalian ◽  
Christopher D. Bertram ◽  
James E. Moore
Keyword(s):  
Blood Circulation ◽  
Lymphatic Vessel ◽  
Lymphatic System ◽  
Lymphatic Vessels ◽  
The Body ◽  
Lumped Parameter Model ◽  
Circulation System ◽  
Blood Circulation System ◽  
Lumped Parameter ◽  
Lymphatic Network

One of the primary functions of the lymphatic system is maintaining fluid and protein balance in the body. The system holds this balance by collecting about four liters of fluid every day from the interstitial space and returning it back to the subclavian vein. In contrast to the blood circulation system that relies on the heart for pumping, there is no central pump in the lymphatic system. Thus, the transport of viscous fluid against gravity and pressure difference occurs by recruiting extrinsic and intrinsic pumping mechanisms. Extrinsic pumping is the transport of lymph due to the movements outside the lymphatic vessel such as the pulse in blood vessels, whereas the intrinsic pumping is transport of lymph by contraction of lymphatic muscle cells embedded in the walls of lymphatic vessels. Similar to the veins, the bi-leaflet valves throughout the lymphatic network prevent backflow. Lymphatic valves are biased open and allow for small amounts of back flow before they completely shut.

scholarly journals lyve1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish

Development ◽  
2012 ◽  
Vol 139 (13) ◽  
pp. 2381-2391 ◽  
Author(s):  
K. S. Okuda ◽  
J. W. Astin ◽  
J. P. Misa ◽  
M. V. Flores ◽  
K. E. Crosier ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Vessel Development

scholarly journals An Unexpected Role of Semaphorin3A–Neuropilin-1 Signaling in Lymphatic Vessel Maturation and Valve Formation

2012 ◽  
Vol 111 (4) ◽  
pp. 426-436 ◽  
Author(s):  
Giorgia Jurisic ◽  
Hélène Maby-El Hajjami ◽  
Sinem Karaman ◽  
Alexandra M. Ochsenbein ◽  
Annamari Alitalo ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Neuropilin 1 ◽  
Vessel Maturation ◽  
Valve Formation
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