scholarly journals Tbx1 regulates Vegfr3 and is required for lymphatic vessel development

2010 ◽  
Vol 189 (3) ◽  
pp. 417-424 ◽  
Author(s):  
Li Chen ◽  
Annalisa Mupo ◽  
Tuong Huynh ◽  
Sara Cioffi ◽  
Matthew Woods ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Perinatal Death ◽  
Major Gene ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Enhancer Element ◽  
Conditional Deletion ◽  
Tumor Lymphangiogenesis ◽  
Vessel Network ◽  
Vessel Development

Lymphatic dysfunction causes several human diseases, and tumor lymphangiogenesis is implicated in cancer spreading. TBX1 is the major gene for DiGeorge syndrome, which is associated with multiple congenital anomalies. Mutation of Tbx1 in mice recapitulates the human disease phenotype. In this study, we use molecular, cellular, and genetic approaches to show, unexpectedly, that Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene. Conditional deletion of Tbx1 in ECs causes widespread lymphangiogenesis defects in mouse embryos and perinatal death. Using the mesentery as a model tissue, we show that Tbx1 is not required for lymphatic EC differentiation; rather, it is required for the growth and maintenance of lymphatic vessels. Our findings reveal a novel pathway for the development of the lymphatic vessel network.

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 MicroRNA-mediated control of developmental lymphangiogenesis

2019 ◽  
Author(s):  
Hyun Min Jung ◽  
Ciara Hu ◽  
Alexandra M. Fister ◽  
Andrew E. Davis ◽  
Daniel Castranova ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Molecular Regulation ◽  
Small Rna Sequencing ◽  
Positive Role ◽  
Vessel Formation ◽  
Lymphatic Development ◽  
Lymphatic Network ◽  
Post Transcriptional Regulation

ABSTRACTThe post-transcriptional mechanisms contributing to molecular regulation of developmental lymphangiogenesis and lymphatic network assembly are not well understood. Here, we use high throughput small RNA sequencing to identify miR-204, a highly conserved miRNA dramatically enriched in lymphatic vs. blood endothelial cells, and we demonstrate that this miRNA plays a critical role during lymphatic development. Suppressing miR-204 leads to loss of lymphatic vessel formation, while overproducing miR-204 in lymphatic vessels accelerates lymphatic vessel formation, suggesting a positive role during developmental lymphangiogenesis. We also identify the NFATC1 transcription factor as a key conserved target for post-transcriptional regulation by miR-204 during lymphangiogenesis. While miR-204 suppression leads to loss of lymphatics, knocking down its target NFATC1 leads to lymphatic hyperplasia, and the loss of lymphatics in miR-204-deficient animals can be rescued by NFATC1 knockdown. Together, our results highlight a miR-204/NFATC1 molecular regulatory axis required for proper lymphatic development.

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

Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3531-3536 ◽  
Author(s):  
Renhai Cao ◽  
Meit A. Björndahl ◽  
Marta I. Gallego ◽  
Shaohua Chen ◽  
Piotr Religa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Blood Vessels ◽  
Lymphatic Metastasis ◽  
Lymphatic Vessel ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Specific Marker ◽  
Indirect Mechanism ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) has previously been reported to act as a hemangiogenic factor, as well as a mitogenic factor for a variety of tumor cells. Here, we demonstrate that HGF is a lymphangiogenic factor, which may contribute to lymphatic metastasis when overexpressed in tumors. In a mouse corneal lymphangiogenesis model, implantation of HGF induces sprouting and growth of new lymphatic vessel expressing the lymphatic vessel endothelial specific marker hyaluronan receptor-1 (Lyve-1). Unlike blood vessels, the Lyve-1–positive structures consist of blunt-ended vessels of large diameters that generally lack expression of CD31. The growth of HGF-induced lymphatic vessels can be partially blocked by a soluble VEGFR-3, suggesting that HGF may stimulate lymphatic vessel growth through an indirect mechanism. Consistent with this finding, the HGF receptor (c-Met) is only localized on corneal blood vessels but is absent on lymphatic vessels in a mouse corneal assay. In a transgenic mouse model that expresses HGF under the control of the whey acidic protein (WAP) gene promoter, transgenic females develop tumors in the mammary glands after several pregnancies. Interestingly, dilated Lyve-1–positive lymphatic vessels accumulate in the peritumoral area and occasionally penetrate into the tumor tissue. Our findings indicate that HGF may play a critical role in lymphangiogenesis and potentially contribute to lymphatic metastasis.

scholarly journals Tbx1 interacts genetically with Vegfr3 to regulate cardiac lymphangiogenesis in mice

2019 ◽  
Author(s):  
Stefania Martucciello ◽  
Maria Giuseppina Turturo ◽  
Sara Cioffi ◽  
Li Chen ◽  
Antonio Baldini ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Genetic Interaction ◽  
Gene Dosage ◽  
Major Gene ◽  
Lymphatic Vessels ◽  
22Q11.2 Deletion Syndrome ◽  
Differential Sensitivity ◽  
Deletion Syndrome ◽  
Loss Of Function ◽  
Compound Heterozygotes

ABSTRACTThe transcription factor TBX1 is the major gene implicated in 22q11.2 deletion syndrome. The complex clinical phenotype includes vascular anomalies and a recent report presented new cases of primary lymphedema in 22q11.2DS patients. We have previously shown that Tbx1 activates Vegfr3 gene expression in lymphatic endothelial cells and that this activation is critical for lymphatic vessel development in prenatal mice and for their survival post-natally. Using loss-of-function genetics and transgenesis, we show a strong genetic interaction between Tbx1 and Vegfr3 in cardiac lymphangiogenesis that causes cardiac lymphatic vessel anomalies in compound heterozygotes. Intriguingly, different aspects of the cardiac lymphatic phenotype were regulated independently by the two genes. Tbx1Cre-activated Vegfr3 transgene expression was able to rescue the morphological abnormalities in the cardiac lymphatic vessels of compound heterozygotes, but it did not rescue the severe cardiac lymphatic vessel hypoplasia observed in Tbx1 homozygotes. Moreover, our study revealed a differential sensitivity between the ventral and dorsal cardiac lymphatic networks to the effects of altered Tbx1 and Vegfr3 gene dosage. Overall, our study demonstrates that a fine dosage balance between Tbx1 and Vegfr3 is required to regulate the number and morphology of cardiac lymphatic vessels.

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.

The contribution of K+ channels to human thoracic duct contractility

2014 ◽  
Vol 307 (1) ◽  
pp. H33-H43 ◽  
Author(s):  
Niklas Telinius ◽  
Sukhan Kim ◽  
Hans Pilegaard ◽  
Einar Pahle ◽  
Jørn Nielsen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Smooth Muscle Cells ◽  
Lymphatic Vessel ◽  
Isometric Force ◽  
Mrna Level ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Muscle Cells ◽  
Resting Membrane Potential

In smooth muscle cells, K+ permeability is high, and this highly influences the resting membrane potential. Lymph propulsion is dependent on phasic contractions generated by smooth muscle cells of lymphatic vessels, and it is likely that K+ channels play a critical role in regulating contractility in this tissue. The aim of this study was to investigate the contribution of distinct K+ channels to human lymphatic vessel contractility. Thoracic ducts were harvested from 43 patients and mounted in a wire myograph for isometric force measurements or membrane potential recordings with an intracellular microelectrode. Using K+ channel blockers and activators, we demonstrate a functional contribution to human lymphatic vessel contractility from all the major classes of K+ channels [ATP-sensitive K+ (KATP), Ca2+-activated K+, inward rectifier K+, and voltage-dependent K+ channels], and this was confirmed at the mRNA level. Contraction amplitude, frequency, and baseline tension were altered depending on which channel was blocked or activated. Microelectrode impalements of lymphatic vessels determined an average resting membrane potential of −43.1 ± 3.7 mV. We observed that membrane potential changes of <5 mV could have large functional effects with contraction frequencies increasing threefold. In general, KATP channels appeared to be constitutively open since incubation with glibenclamide increased contraction frequency in spontaneously active vessels and depolarized and initiated contractions in previously quiescent vessels. The largest change in membrane voltage was observed with the KATP opener pinacidil, which caused 24 ± 3 mV hyperpolarization. We conclude that K+ channels are important modulators of human lymphatic contractility.

scholarly journals Lymphatic Endothelial Markers and Tumor Lymphangiogenesis Assessment in Human Breast Cancer

Diagnostics ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 4
Author(s):  
Jia-Mei Chen ◽  
Bo Luo ◽  
Ru Ma ◽  
Xi-Xi Luo ◽  
Yong-Shun Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Human Breast Cancer ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Predictive Biomarkers ◽  
Lymphatic Endothelial Cell ◽  
Research Progress ◽  
Human Breast ◽  
Tumor Lymphangiogenesis

Metastasis via lymphatic vessels or blood vessels is the leading cause of death for breast cancer, and lymphangiogenesis and angiogenesis are critical prerequisites for the tumor invasion–metastasis cascade. The research progress for tumor lymphangiogenesis has tended to lag behind that for angiogenesis due to the lack of specific markers. With the discovery of lymphatic endothelial cell (LEC) markers, growing evidence demonstrates that the LEC plays an active role in lymphatic formation and remodeling, tumor cell growth, invasion and intravasation, tumor–microenvironment remodeling, and antitumor immunity. However, some studies have drawn controversial conclusions due to the variation in the LEC markers and lymphangiogenesis assessments used. In this study, we review recent findings on tumor lymphangiogenesis, the most commonly used LEC markers, and parameters for lymphangiogenesis assessments, such as the lymphatic vessel density and lymphatic vessel invasion in human breast cancer. An in-depth understanding of tumor lymphangiogenesis and LEC markers can help to illustrate the mechanisms and distinct roles of lymphangiogenesis in breast cancer progression, which will help in exploring novel potential predictive biomarkers and therapeutic targets for breast cancer.

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