scholarly journals YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

Development ◽  
2020 ◽  
Vol 147 (23) ◽  
pp. dev195453
Author(s):  
Boksik Cha ◽  
Yen-Chun Ho ◽  
Xin Geng ◽  
Md. Riaj Mahamud ◽  
Lijuan Chen ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Valve Development ◽  
Prox1 Expression ◽  
Homeobox Transcription Factor ◽  
Lymphatic Vasculature ◽  
Factor C ◽  
Endothelial Growth Factor ◽  
First Time

ABSTRACTLymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C, YAP and TAZ as a crucial molecular pathway in valve development.

VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development

Development ◽  
1996 ◽  
Vol 122 (12) ◽  
pp. 3829-3837 ◽  
Author(s):  
E. Kukk ◽  
A. Lymboussaki ◽  
S. Taira ◽  
A. Kaipainen ◽  
M. Jeltsch ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lymphatic Vessels ◽  
Mouse Lung ◽  
Vascular Endothelial ◽  
Related Factors ◽  
C Protein ◽  
Lymphatic Vasculature ◽  
Endothelial Growth Factor

The vascular endothelial growth factor family has recently been expanded by the isolation of two new VEGF-related factors, VEGF-B and VEGF-C. The physiological functions of these factors are largely unknown. Here we report the cloning and characterization of mouse VEGF-C, which is produced as a disulfide-linked dimer of 415 amino acid residue polypeptides, sharing an 85% identity with the human VEGF-C amino acid sequence. The recombinant mouse VEGF-C protein was secreted from transfected cells as VEGFR-3 (Flt4) binding polypeptides of 30–32x10(3) Mr and 22–23x10(3) Mr which preferentially stimulated the autophosphorylation of VEGFR-3 in comparison with VEGFR-2 (KDR). In in situ hybridization, mouse VEGF-C mRNA expression was detected in mesenchymal cells of postimplantation mouse embryos, particularly in the regions where the lymphatic vessels undergo sprouting from embryonic veins, such as the perimetanephric, axillary and jugular regions. In addition, the developing mesenterium, which is rich in lymphatic vessels, showed strong VEGF-C expression. VEGF-C was also highly expressed in adult mouse lung, heart and kidney, where VEGFR-3 was also prominent. The pattern of expression of VEGF-C in relation to its major receptor VEGFR-3 during the sprouting of the lymphatic endothelium in embryos suggests a paracrine mode of action and that one of the functions of VEGF-C may be in the regulation of angiogenesis of the lymphatic vasculature.

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.

scholarly journals Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5650-5659 ◽  
Author(s):  
Raghu P. Kataru ◽  
Keehoon Jung ◽  
Cholsoon Jang ◽  
Hanseul Yang ◽  
Reto A. Schwendener ◽  
...  
Keyword(s):  
Critical Role ◽  
Lymphatic Vessels ◽  
Bacterial Pathogen ◽  
Inflammatory Cells ◽  
Vascular Endothelial ◽  
Factor C ◽  
Inflammation Resolution ◽  
Endothelial Growth Factor ◽  
Draining Lymph Nodes

Using a bacterial pathogen–induced acute inflammation model in the skin, we defined the roles of local lymphatic vessels and draining lymph nodes (DLNs) in antigen clearance and inflammation resolution. At the peak day of inflammation, robust expansion of lymphatic vessels and profound infiltration of CD11b+/Gr-1+ macrophages into the inflamed skin and DLN were observed. Moreover, lymph flow and inflammatory cell migration from the inflamed skin to DLNs were enhanced. Concomitantly, the expression of lymphangiogenic growth factors such as vascular endothelial growth factor C (VEGF-C), VEGF-D, and VEGF-A were significantly up-regulated in the inflamed skin, DLNs, and particularly in enriched CD11b+ macrophages from the DLNs. Depletion of macrophages, or blockade of VEGF-C/D or VEGF-A, largely attenuated these phenomena, and produced notably delayed antigen clearance and inflammation resolution. Conversely, keratin 14 (K14)–VEGF-C transgenic mice, which have dense and enlarged lymphatic vessels in the skin dermis, exhibited accelerated migration of inflammatory cells from the inflamed skin to the DLNs and faster antigen clearance and inflammation resolution. Taken together, these results indicate that VEGF-C, -D, and -A derived from the CD11b+/Gr-1+ macrophages and local inflamed tissues play a critical role in promoting antigen clearance and inflammation resolution.

scholarly journals The Roles of Non-Coding RNAs in Tumor-Associated Lymphangiogenesis

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3290
Author(s):  
Khairunnisa’ Md Yusof ◽  
Rozita Rosli ◽  
Maha Abdullah ◽  
Kelly A. Avery-Kiejda
Keyword(s):  
Growth Factor ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Lymphatic Circulation ◽  
Tumor Lymphangiogenesis ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
Non Coding Rnas ◽  
Endothelial Growth Factor ◽  
Regulation Of Growth

Lymphatic vessels are regarded as the ”forgotten” circulation. Despite this, growing evidence has shown significant roles for the lymphatic circulation in normal and pathological conditions in humans, including cancers. The dissemination of tumor cells to other organs is often mediated by lymphatic vessels that serve as a conduit and is often referred to as tumor-associated lymphangiogenesis. Some of the most well-studied lymphangiogenic factors that govern tumor lymphangiogenesis are the vascular endothelial growth factor (VEGF-C/D and VEGFR-2/3), neuroplilin-2 (NRP2), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), to name a few. However, recent findings have illustrated that non-coding RNAs are significantly involved in regulating gene expression in most biological processes, including lymphangiogenesis. In this review, we focus on the regulation of growth factors and non-coding RNAs (ncRNAs) in the lymphatic development in normal and cancer physiology. Then, we discuss the lymphangiogenic factors that necessitate tumor-associated lymphangiogenesis, with regards to ncRNAs in various types of cancer. Understanding the different roles of ncRNAs in regulating lymphatic vasculature in normal and cancer conditions may pave the way towards the development of ncRNA-based anti-lymphangiogenic therapy.

scholarly journals Spreds Are Essential for Embryonic Lymphangiogenesis by Regulating Vascular Endothelial Growth Factor Receptor 3 Signaling

2007 ◽  
Vol 27 (12) ◽  
pp. 4541-4550 ◽  
Author(s):  
Koji Taniguchi ◽  
Ri-ichiro Kohno ◽  
Toranoshin Ayada ◽  
Reiko Kato ◽  
Kenji Ichiyama ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Lymphatic Vessels ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Erk Activation ◽  
Factor C ◽  
Endothelial Growth Factor

ABSTRACT Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk −/− and SLP-76 −/− mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.

scholarly journals Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting

2007 ◽  
Vol 204 (6) ◽  
pp. 1431-1440 ◽  
Author(s):  
Maria Wirzenius ◽  
Tuomas Tammela ◽  
Marko Uutela ◽  
Yulong He ◽  
Teresa Odorisio ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Mouse Skin ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Factor C ◽  
Endothelial Growth Factor

Lymphatic vessel growth, or lymphangiogenesis, is regulated by vascular endothelial growth factor-C (VEGF-C) and -D via VEGF receptor 3 (VEGFR-3). Recent studies suggest that VEGF, which does not bind to VEGFR-3, can also induce lymphangiogenesis through unknown mechanisms. To dissect the receptor pathway that triggers VEGFR-3–independent lymphangiogenesis, we used both transgenic and adenoviral overexpression of placenta growth factor (PlGF) and VEGF-E, which are specific activators of VEGFR-1 and -2, respectively. Unlike PlGF, VEGF-E induced circumferential lymphatic vessel hyperplasia, but essentially no new vessel sprouting, when transduced into mouse skin via adenoviral vectors. This effect was not inhibited by blocking VEGF-C and -D. Postnatal lymphatic hyperplasia, without increased density of lymphatic vessels, was also detected in transgenic mice expressing VEGF-E in the skin, but not in mice expressing PlGF. Surprisingly, VEGF-E induced lymphatic hyperplasia postnatally, and it did not rescue the loss of lymphatic vessels in transgenic embryos where VEGF-C and VEGF-D were blocked. Our data suggests that VEGFR-2 signals promote lymphatic vessel enlargement, but unlike in the blood vessels, are not involved in vessel sprouting to generate new lymphatic vessels in vivo.

scholarly journals Two Birds, One Stone: Double Hits on Tumor Growth and Lymphangiogenesis by Targeting Vascular Endothelial Growth Factor Receptor 3

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 270 ◽  
Author(s):  
Ming-Chuan Hsu ◽  
Mei-Ren Pan ◽  
Wen-Chun Hung
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Lymphatic Metastasis ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Factor C ◽  
Endothelial Growth Factor

: Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of VEGF-C/VEGFR3 signaling in lymphatic endothelial cells (LECs) was shown to enhance the proliferation of LECs and the formation of lymphatic vessels, leading to increased lymphatic metastasis of tumor cells. In the past decade, the expression and pathological roles of VEGFR3 in tumor cells have been described. Moreover, the VEGF-C/VEGFR3 axis has been implicated in regulating immune tolerance and suppression. Therefore, the inhibition of the VEGF-C/VEGFR3 axis has emerged as an important therapeutic strategy for the treatment of cancer. In this review, we discuss the current findings related to VEGF-C/VEGFR3 signaling in cancer progression and recent advances in the development of therapeutic drugs targeting VEGF-C/VEGFR3.

Lymphangiogenic growth factors, receptors and therapies

2003 ◽  
Vol 90 (08) ◽  
pp. 167-184 ◽  
Author(s):  
Marja Lohela ◽  
Anne Saaristo ◽  
Tanja Veikkola ◽  
Kari Alitalo
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Factor C ◽  
Endothelial Growth Factor

SummaryThe lymphatic vasculature is essential for the maintenance of normal fluid balance and for the immune responses, but it is also involved in a variety of diseases. Hypoplasia or dysfuction of the lymphatic vessels can lead to lymphedema, whereas hyperplasia or abnormal growth of these vessels are associated with lymphangiomas and lymphangiosarcomas. Lymphatic vessels are also involved in lymph node and systemic metastasis of cancer cells. Recent novel findings on the molecular mechanisms involved in lymphatic vessel development and regulation allow the modulation of the lymphangiogenic process and specific targeting of the lymphatic endothelium.Recent results show that the homeodomain transcription factor Prox-1 is an important lymphatic endothelial cell (LEC) fate-determining factor which can induce LEC-specific gene transcription even in blood vascular endothelial cells (BECs). This suggests that the distinct phenotypes of cells in the adult vascular endothelium are plastic and sensitive to transcriptional reprogramming, which might be useful for future therapeutic applications involving endothelial cellsVascular endothelial growth factor-C (VEGF-C) and VEGF-D are peptide growth factors capable of inducing the growth of new lymphatic vessels in vivo in a process called lymphangiogenesis. They belong to the larger family which also includes VEGF, placenta growth factor (PlGF) and VEGF-B. VEGF-C and VEGF-D are ligands for the endothelial cell specific tyrosine kinase receptors VEGFR-2 and VEGFR-3. In adult human as well as mouse tissues VEGFR-3 is expressed predominantly in lymphatic endothelial cells which line the inner surface of lymphatic vessels. While VEGFR-2 is thought to be the main mediator of angiogenesis, VEGFR-3 signaling is crucial for the development of the lymphatic vessels. Heterozygous inactivation of the VEGFR-3 tyrosine kinase leads to primary lymphedema due to defective lymphatic drainage in the limbs. Other factors that seem to be involved in lymphangiogenesis include the Tie/angiopoietin system, neuropilin-2 and integrin α9.VEGF-C induces lymphatic vessel growth, but high levels of VEGF-C also resulted in blood vessel leakiness and growth. The VEGFR-3-specific mutant form of VEGF-C called VEGF-C156S lacks blood vascular side effects but is sufficient for therapeutic lymphangiogenesis in a mouse model of lymphedema. As VEGF-C156S is a specific lymphatic endothelial growth factor in the skin, it provides an attractive molecule for pro-lymphangiogenic therapy.This publication was partially financed by Serono. Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology, which took place in Geneva, Switzerland from February 6-9, 2003.

scholarly journals Topical VEGF-C/D Inhibition Prevents Lymphatic Vessel Ingrowth into Cornea but Does Not Improve Corneal Graft Survival

2020 ◽  
Vol 9 (5) ◽  
pp. 1270
Author(s):  
Ann-Charlott Salabarria ◽  
Manuel Koch ◽  
Alfrun Schönberg ◽  
Elisabeth Zinser ◽  
Deniz Hos ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
High Risk ◽  
Immune Cells ◽  
Lymphatic Vessel ◽  
Corneal Transplantation ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Factor C ◽  
Endothelial Growth Factor

Vascular endothelial growth factor-C/D (VEGF-C/D) regulates lymphangiogenesis. Ingrowth of lymphatic vessels is negatively associated with corneal transplantation success. In this study, we therefore analyzed the effect local blockade of VEGF-C/D has on inflamed corneas. We used the murine model of suture-induced neovascularization and subsequent high-risk corneal transplantation. Mice were treated with a VEGF-C/D trap prior to transplantation. Topical inhibition of VEGF-C/D significantly reduced lymphatic vessel ingrowth, but increased Macrophage numbers in the cornea. Furthermore, corneal transplantation success was not improved by the topical application of the compound. This study demonstrates that local VEGF-C/D inhibition is insufficient to increases corneal transplantation success, likely due to interaction with immune cells.

Sign in / Sign up

Export Citation Format

Share Document