Angiopoietin-1 promotes lymphatic sprouting and hyperplasia

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4642-4648 ◽  
Author(s):  
Tuomas Tammela ◽  
Anne Saaristo ◽  
Marja Lohela ◽  
Tohru Morisada ◽  
Jenny Tornberg ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Viral Vectors ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Soluble Form ◽  
Tissue Edema ◽  
Mouse Tissues ◽  
Vessel Development ◽  
Endothelial Growth Factor ◽  
Angiopoietin 1

Abstract Angiopoietin 1 (Ang1), a ligand for the receptor tyrosine kinase Tie2, regulates the formation and stabilization of the blood vessel network during embryogenesis. In adults, Ang1 is associated with blood vessel stabilization and recruitment of perivascular cells, whereas Ang2 acts to counter these actions. Recent results from gene-targeted mice have shown that Ang2 is also essential for the proper patterning of lymphatic vessels and that Ang1 can be substituted for this function. In order to characterize the effects of the angiopoietins on lymphatic vessels, we employed viral vectors for overexpression of Ang1 in adult mouse tissues. We found that Ang1 activated lymphatic vessel endothelial proliferation, vessel enlargement, and generation of long endothelial cell filopodia that eventually fused, leading to new sprouts and vessel development. Cutaneous lymphatic hyperplasia was also detected in transgenic mice expressing Ang1 in the basal epidermal cells. Tie2 was expressed in the lymphatic endothelial cells and Ang1 stimulation of these cells resulted in up-regulation of vascular endothelial growth factor receptor 3 (VEGFR-3). Furthermore, a soluble form of VEGFR-3 inhibited the observed lymphatic sprouting. Our results reinforce the concept that Ang1 therapy may be useful in settings of tissue edema. (Blood. 2005;105:4642-4648)

The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1989-1997 ◽  
Author(s):  
Kyle Niessen ◽  
Gu Zhang ◽  
John Brady Ridgway ◽  
Hao Chen ◽  
Ganesh Kolumam ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Lymphatic Vessels ◽  
Mouse Skin ◽  
Notch Signaling Pathway ◽  
Cell Phenotype ◽  
Mural Cell ◽  
Lymphatic Development ◽  
Vessel Development

Abstract The Notch signaling pathway plays a fundamental role during blood vessel development. Notch signaling regulates blood vessel morphogenesis by promoting arterial endothelial differentiation and pro-viding spatial and temporal control over “tip cell” phenotype during angiogenic sprouting. Components of the Notch signaling pathway have emerged as potential regulators of lymphatic development, joining the increasing examples of blood vessel regulators that are also involved in lymphatic development. However, in mammals a role for the Notch signaling pathway during lymphatic development remains to be demonstrated. In this report, we show that blockade of Notch1 and Dll4, with specific function-blocking antibodies, results in defective postnatal lymphatic development in mice. Mechanistically, Notch1-Dll4 blockade is associated with down-regulation of EphrinB2 expression, been shown to be critically involved in VEGFR3/VEGFC signaling, resulting in reduced lymphangiogenic sprouting. In addition, Notch1-Dll4 blockade leads to compromised expression of distinct lymphatic markers and to dilation of collecting lymphatic vessels with reduced and disorganized mural cell coverage. Finally, Dll4-blockade impairs wound closure and severely affects lymphangiogenesis during the wound healing in adult mouse skin. Thus, our study demonstrates for the first time in a mammalian system that Notch1-Dll4 signaling pathway regulates postnatal lymphatic development and pathologic lymphangiogenesis.

Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1154-1162 ◽  
Author(s):  
Wei Zheng ◽  
Tuomas Tammela ◽  
Masahiro Yamamoto ◽  
Andrey Anisimov ◽  
Tanja Holopainen ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Notch Pathway ◽  
Lymphatic Vessels ◽  
Soluble Form ◽  
Fibrin Gel ◽  
3 Dimensional ◽  
Endothelial Growth Factor

Abstract Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.

scholarly journals FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1611
Author(s):  
Ningfei Liu ◽  
Minzhe Gao
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Clinical Signs ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
History Of ◽  
Endothelial Growth Factor

This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.

Measurement of free and complexed soluble vascular endothelial growth factor receptor, Flt-1, in fluid samples: development and application of two new immunoassays

2001 ◽  
Vol 100 (5) ◽  
pp. 567-575 ◽  
Author(s):  
Funmi M. BELGORE ◽  
Andrew D. BLANN ◽  
Gregory Y. LIP
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Plasma Levels ◽  
Biological Significance ◽  
Growth Factor Receptor ◽  
Soluble Form ◽  
Vascular Endothelial ◽  
Significant Difference ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. VEGF interacts with the endothelium via two membrane-spanning receptors, fms-like tyrosine kinase (Flt)-1 and kinase domain receptor. A soluble form of Flt-1 (sFlt-1) was isolated from endothelial cell media; however, its biological significance is still unknown, with limited data on plasma sFlt-1 levels in disease states. We have developed two new ELISAs for detecting free and VEGF-complexed sFlt-1, which were tested in accordance with standard validation and assessment methodologies employed in commercial settings. The intra-and inter-assay coefficients of variation are < 5% and 10% respectively, and results are highly reproducible. Applying these ELISAs in a clinical setting, we measured levels of VEGF, free and complexed sFlt-1 in citrated plasma from 40 patients with cardiovascular disease and 40 healthy controls. Median (interquartile range) plasma levels of VEGF in patients were significantly greater than controls [403 pg/ml (158–925 pg/ml) versus 113 pg/ml (33–231 pg/ml), P ⩽ 0.05]. Free sFlt-1 was significantly lower in patients compared with controls [8 ng/ml (2–22 ng/ml) versus 21 ng/ml (10–73 ng/ml), P ⩽ 0.05]. There was no significant difference in the levels of complexed sFlt-1 between the two groups. Plasma levels of VEGF-complexed sFlt-1 are minimal, despite the presence of excess free sFlt-1. Thus unbound plasma VEGF detected by ELISA may represent the majority of circulating VEGF, and justifies the measurement of plasma VEGF as an indicator of circulating VEGF levels. Furthermore, these results suggest that circulating sFlt-1 may serve as a selective inhibitor of VEGF activity, and that this regulatory mechanism may be altered by pathological conditions.

scholarly journals Impaired meningeal lymphatic vessel development worsens stroke outcome

2019 ◽  
Vol 40 (2) ◽  
pp. 263-275 ◽  
Author(s):  
Pavel Yanev ◽  
Katherine Poinsatte ◽  
Devon Hominick ◽  
Noor Khurana ◽  
Kielen R Zuurbier ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Young Male ◽  
Artery Occlusion ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Sagittal Sinus ◽  
The Central Nervous System ◽  
Vessel Development ◽  
The Impact

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3wt/mut mice develop significantly fewer meningeal LVs than Vegfr3wt/wt mice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke in Vegfr3wt/wt mice. Interestingly, Vegfr3wt/mut mice develop larger stroke volumes than Vegfr3wt/wt mice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes.

scholarly journals Vascular Endothelial Growth Factor D Is Dispensable for Development of the Lymphatic System

2005 ◽  
Vol 25 (6) ◽  
pp. 2441-2449 ◽  
Author(s):  
Megan E. Baldwin ◽  
Michael M. Halford ◽  
Sally Roufail ◽  
Richard A. Williams ◽  
Margaret L. Hibbs ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Tissue Mass ◽  
And Function ◽  
Endothelial Growth Factor ◽  
Deficient Mice

ABSTRACT Vascular endothelial growth factor receptor 3 (Vegfr-3) is a tyrosine kinase that is expressed on the lymphatic endothelium and that signals for the growth of the lymphatic vessels (lymphangiogenesis). Vegf-d, a secreted glycoprotein, is one of two known activating ligands for Vegfr-3, the other being Vegf-c. Vegf-d stimulates lymphangiogenesis in tissues and tumors; however, its role in embryonic development was previously unknown. Here we report the generation and analysis of mutant mice deficient for Vegf-d. Vegf-d-deficient mice were healthy and fertile, had normal body mass, and displayed no pathologic changes consistent with a defect in lymphatic function. The lungs, sites of strong Vegf-d gene expression during embryogenesis in wild-type mice, were normal in Vegf-d-deficient mice with respect to tissue mass and morphology, except that the abundance of the lymphatics adjacent to bronchioles was slightly reduced. Dye uptake experiments indicated that large lymphatics under the skin were present in normal locations and were functional. Smaller dermal lymphatics were similar in number, location, and function to those in wild-type controls. The lack of a profound lymphatic phenotype in Vegf-d-deficient mice suggests that Vegf-d does not play a major role in lymphatic development or that Vegf-c or another, as-yet-unknown activating Vegfr-3 ligand can compensate for Vegf-d during development.

scholarly journals A simple detection method for the serum sFLT1 protein in preeclampsia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masabumi Shibuya ◽  
Haruka Matsui ◽  
Tadashi Sasagawa ◽  
Takeshi Nagamatsu
Keyword(s):  
Low Cost ◽  
Growth Factor Receptor ◽  
Normal Pregnancy ◽  
Soluble Form ◽  
Vascular Endothelial ◽  
Pathological Conditions ◽  
Abnormal Increase ◽  
Simple Detection ◽  
Sandwich Type ◽  
Endothelial Growth Factor

AbstractIn normal pregnancy, the soluble form of FMS-like tyrosine kinase-1 (sFLT1)/ vascular endothelial growth factor receptor-1 (sVEGFR-1), a VEGF-trapping protein, is expressed in trophoblasts of the placenta, suggesting that it plays an important role in the physiological barrier between fetal and maternal angiogenesis, when stimulated with VEGF-A. In pathological conditions such as preeclampsia (PE), sFLT1 protein is abnormally overexpressed in trophoblasts and secreted into the serum, which could cause hypertension and proteinuria on the maternal side and growth retardation on the fetal side. Detection of an abnormal increase in serum sFLT1 during the early to middle stages of PE is essential for proper initiation of medical care. To carry out this screening for sFLT1, we developed an easier and relatively low-cost sandwich-type ELISA method using a single mixture of human serum sample with an anti-FLT1 antibody and heparin-beads, namely heparin-beads-coupled ELISA (HB-ELISA). This method takes only about 2 h, and the sFLT1 values were similar levels with commercially available recent ELISA kits: the serum sFLT1 protein was approximately 4.3-fold increased in severe PE compared with those in normal pregnancy.

Inhibition of Angiogenesis by a Novel Neutralizing Antibody Against Human Vascular Endothelial Growth Factor Receptor 3 (VEGFR-3).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3968-3968
Author(s):  
Hao Chen ◽  
Xiu-Yun Ding ◽  
Yuan Gao ◽  
Fei-Yao Ren ◽  
Hui Li ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Neutralizing Antibody ◽  
Vascular Endothelial ◽  
Hel Cells ◽  
Factor C ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligands, vascular endothelial growth factor-C (VEGF-C) and D (VEGF-D), are the major molecules involved in the development of the embryonic vascular system and pathological lymphangiogenesis. Throughout embryogenesis, VEGFR-3 is expressed in most endothelial cells, whilst being restricted to lymphatic vessels later in development. This receptor plays a significant role in the normal development of blood and lymphatic vessels. In the present studies, we generated a novel panel of 17 monoclonal antibodies (mAbs) against the human VEGFR-3 and characterized their ability to inhibit the proliferation of human erythroleukemia (HEL) cells and angiogenesis of chick embryo chorioallantoic membrane (CAM). Among these mAbs, BDD073 was demonstrated to inhibit the interaction of soluble VEGFR-3 with VEGF-D and the proliferation of HEL cells. In CAM angiogenesis experiments, the angiogenesis induced by recombinant GST-VEGF-D was decreased in the presence of antibody BDD073. These data indicate that this novel neutralizing antibody against human VEGFR-3 not only might be a potential compounds in blocking the VEGF-D-induced angiogenesis and lymphangiogenesis, but also be a tool for the investigations of biology of VEGFR-3 and analysis of lymphatic vessels in malignant tumors and their metastases.

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