scholarly journals Role of synectin in lymphatic development in zebrafish and frogs

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3356-3366 ◽  
Author(s):  
Karlien Hermans ◽  
Filip Claes ◽  
Wouter Vandevelde ◽  
Wei Zheng ◽  
Ilse Geudens ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Thoracic Duct ◽  
Pdz Domain ◽  
Lymphatic Endothelial Cells ◽  
Cardinal Vein ◽  
Morpholino Knockdown ◽  
Lymphatic Development ◽  
Factor C ◽  
Endothelial Growth Factor

Abstract The molecular basis of lymphangiogenesis remains incompletely characterized. Here, we document a novel role for the PDZ domain-containing scaffold protein synectin in lymphangiogenesis using genetic studies in zebrafish and tadpoles. In zebrafish, the thoracic duct arises from parachordal lymphangioblast cells, which in turn derive from secondary lymphangiogenic sprouts from the posterior cardinal vein. Morpholino knockdown of synectin in zebrafish impaired formation of the thoracic duct, due to selective defects in lymphangiogenic but not angiogenic sprouting. Synectin genetically interacted with Vegfr3 and neuropilin-2a in regulating lymphangiogenesis. Silencing of synectin in tadpoles caused lymphatic defects due to an underdevelopment and impaired migration of Prox-1+ lymphatic endothelial cells. Molecular analysis further revealed that synectin regulated Sox18-induced expression of Prox-1 and vascular endothelial growth factor C–induced migration of lymphatic endothelial cells in vitro. These findings reveal a novel role for synectin in lymphatic development.

scholarly journals Netrin-4 induces lymphangiogenesis in vivo

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5418-5426 ◽  
Author(s):  
Frederic Larrieu-Lahargue ◽  
Alana L. Welm ◽  
Kirk R. Thomas ◽  
Dean Y. Li
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
Tumor Dissemination ◽  
Factor C ◽  
Endothelial Growth Factor

Abstract Netrin-4, a laminin-related secreted protein is an axon guidance cue recently shown essential outside of the nervous system, regulating mammary and lung morphogenesis as well as blood vascular development. Here, we show that Netrin-4, at physiologic doses, induces proliferation, migration, adhesion, tube formation and survival of human lymphatic endothelial cells in vitro comparable to well-characterized lymphangiogenic factors fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF), vascular endothelial growth factor-A (VEGF-A), and vascular endothelial growth factor-C (VEGF-C). Netrin-4 stimulates phosphorylation of intracellular signaling components Akt, Erk and S6, and their specific inhibition antagonizes Netrin-4–induced proliferation. Although Netrin receptors Unc5B and neogenin, are expressed by human lymphatic endothelial cells, suppression of either or both does not suppress Netrin-4–promoted in vitro effects. In vivo, Netrin-4 induces growth of lymphatic and blood vessels in the skin of transgenic mice and in breast tumors. Its overexpression in human and mouse mammary carcinoma cancer cells leads to enhanced metastasis. Finally, Netrin-4 stimulates in vitro and in vivo lymphatic permeability by activating small GTPases and Src family kinases/FAK, and down-regulating tight junction proteins. Together, these data provide evidence that Netrin-4 is a lymphangiogenic factor contributing to tumor dissemination and represents a potential target to inhibit metastasis formation.

scholarly journals Isolation and Characterisation of Lymphatic Endothelial Cells from Lung Tissues Affected by Lymphangioleiomyomatosis

2021 ◽  
Author(s):  
Koichi Nishino ◽  
Yasuhiro Yoshimatsu ◽  
Tomoki Muramatsu ◽  
Yasuhito Sekimoto ◽  
Keiko Mitani ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Normal Lung ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
And Migration ◽  
Endothelial Growth Factor ◽  
Proliferation And Migration

Abstract Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

scholarly journals ALK1 signaling regulates early postnatal lymphatic vessel development

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1654-1661 ◽  
Author(s):  
Kyle Niessen ◽  
Gu Zhang ◽  
John Brady Ridgway ◽  
Hao Chen ◽  
Minhong Yan
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Lymphatic Endothelial Cells ◽  
Multiple Organs ◽  
Lymphatic Development

Abstract In vertebrates, endothelial cells form 2 hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the transforming growth factor-β type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of the ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We find that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.

scholarly journals Jin Fu Kang Oral Liquid Inhibits Lymphatic Endothelial Cells Formation and Migration

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Hai-Lang He ◽  
Dan Wang ◽  
Jie Tang ◽  
Xian-Mei Zhou ◽  
Jian-Xin Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Endothelial Cells ◽  
Lymphatic Endothelial Cells ◽  
Inhibitory Effects ◽  
Oral Liquid ◽  
Chinese Herbal Drugs ◽  
Stromal Cell Derived Factor ◽  
And Migration ◽  
Factor C ◽  
Endothelial Growth Factor

Lung cancer is the leading cause of cancer-related deaths worldwide. Jin Fu Kang (JFK), an oral liquid prescription of Chinese herbal drugs, has been clinically available for the treatment of non-small cell lung cancer (NSCLC). Lymphangiogenesis is a primary event in the process of cancer development and metastasis, and the formation and migration of lymphatic endothelial cells (LECs) play a key role in the lymphangiogenesis. To assess the activity of stromal cell-derived factor-1 (SDF-1) and the coeffect of SDF-1 and vascular endothelial growth factor-C (VEGF-C) on the formation and migration of LECs and clarify the inhibitory effects of JFK on the LECs, the LECs were differentiated from CD34+/VEGFR-3+endothelial progenitor cells (EPCs), and JFK-containing serums were prepared from rats. SDF-1 and VEGF-C both induced the differentiation of CD34+/VEGFR-3+EPCs towards LECs and enhanced the LECs migration. Couse of SDF-1 and VEGF-C displayed an additive effect on the LECs formation but not on their migration. JFK inhibited the formation and migration of LECs, and the inhibitory effects were most probably via regulation of the SDF-1/CXCR4 and VEGF-C/VEGFR-3 axes. The current finding suggested that JFK might inhibit NSCLC through antilymphangiogenesis and also provided a potential to discover antilymphangiogenesis agents from natural resources.

scholarly journals Vascular endothelial growth factor-C enhances radiosensitivity of lymphatic endothelial cells

Angiogenesis ◽  
2013 ◽  
Vol 17 (2) ◽  
pp. 419-427 ◽  
Author(s):  
Cristina T. Kesler ◽  
Angera H. Kuo ◽  
Hon-Kit Wong ◽  
David J. Masuck ◽  
Jennifer L. Shah ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
Factor C ◽  
Endothelial Growth Factor

scholarly journals Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma

2021 ◽  
Vol 118 (19) ◽  
pp. e2019580118
Author(s):  
Naofumi Yoshida ◽  
Seiji Yamamoto ◽  
Takeru Hamashima ◽  
Noriko Okuno ◽  
Naruho Okita ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Cystic Lymphangioma ◽  
Dermal Fibroblasts ◽  
Lymphatic Endothelial Cells ◽  
Dual Source ◽  
Factor Type ◽  
Factor C

Along with blood vessels, lymphatic vessels play an important role in the circulation of body fluid and recruitment of immune cells. Postnatal lymphangiogenesis commonly occurs from preexisting lymphatic vessels by sprouting, which is induced by lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C). However, the key signals and cell types that stimulate pathological lymphangiogenesis, such as human cystic lymphangioma, are less well known. Here, we found that mouse dermal fibroblasts that infiltrate to sponges subcutaneously implanted express VEGF-D and sushi, Von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) in response to PDGFRβ signal. In vitro, Pdgfrb knockout (β-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the β-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblast-derived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.

scholarly journals Lymphatic Network and Lymphangiogenesis in the Gastric Wall

2003 ◽  
Vol 51 (3) ◽  
pp. 331-338 ◽  
Author(s):  
Rui-Cheng Ji ◽  
Seiji Kato
Keyword(s):  
Endothelial Cells ◽  
Gastric Wall ◽  
Morphological Properties ◽  
Vascular Endothelial ◽  
Lymph Drainage ◽  
Lymphatic Development ◽  
Early Embryonic Stage ◽  
Lymphatic Network ◽  
Factor C ◽  
Endothelial Growth Factor

A family of growth factors highly specific for endothelial cells was identified more than 10 years ago, in which the receptor of vascular endothelial growth factor C (VEGFR-3) is implicated in the regulation of lymphatic development and regeneration. Comparative studies on the lymphatic network and lymphangiogenesis have been done mainly using combined 5′-nucleotidase (5′-Nase) enzyme and VEGFR-3 immunohistochemical approaches in adult and fetal gastric walls. Developing lymphatic networks represented fewer blind ends and branches than mature networks in whole-mount preparations. Many circular lymphatic-like structures exhibited VEGFR-3 expression and weak 5′-Nase activity in the early embryonic stage, showing visible morphological properties in the lymphatic endothelium. These newly formed lymphatics showed an obvious accumulation in the submucosa and serosa and a variation in the intensity of VEGFR-3 binding to endothelial cells among samples. A reaction product for anti-VEGFR-3 was found on the luminal surface of endothelial cells and on the membrane of some organelles and intraluminal lymphocytes. These findings indicate that an active proliferating feature of the clustered developing lymphatics may create a favorable environment for their sprouting and growth, which may serve as a functional requirement for lymph drainage in the region.

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