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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study has investigated the relationship between pancreatic lymphatics, infiltrating cells, and insulitic development after a single injection of complete Freund's adjuvant (CFA) given at an early age in the nonobese diabetic (NOD) mice. No CFA-treated NOD mice developed hyperglycemia, whereas most CFA-untreated mice died of diabetes at the age of 20-30 weeks. In untreated NOD mice, the increased infiltration of dendritic cells (DCs) and T-lymphocytes into the pancreatic islets appeared to be consistent with the increased expression of the secondary lymphoid chemokine (CCL21) and CD(31) by the endothelial cell lining of inter- and intralobular lymphatics. As the infiltration became severe, the reaction products of CCL21 and CD(31) were distributed in the nucleus and cytoplasm of lymphatic endothelial cells (LECs), through which DCs and T-lymphocytes migrated frequently. Administration of CFA reduced the number of infiltrating DCs and T-lymphocytes, but did not affect macrophage infiltration. The peri-insulitis occurred in numerous islets of CFA-treated NOD mice without the appearance of the intraislet infiltration and islet-associated lymphoid-like tissues. Furthermore, significant suppression of CCL21 and CD(31) was demonstrated on the infiltrating cells to the islets and islet-associated lymphatics. The abluminal endothelial cell lining of lymphatic vessels exhibited weaker immunoreactivity of CCL21 and CD(31) in comparison with the luminal surfaces. The reaction product of 5'-nucleotidase (5'-Nase) was evenly deposited on LECs, which were the absence of open junctions, cytoplasmic protrusions, and vesicles. CFA treatment influenced the migratory processes of the infiltrating cell, which were closely related with structural changes of pancreatic lymphatics and inhibited insulitic development. These findings suggest that in CFA-treated NOD mice, the suppression of insulitis and prevention of diabetes are secondary to the functional modulation of pancreatic lymphatics and infiltrating cells.
Anat Rec A Discov Mol Cell Evol Biol 2004 Dec
PMID:Study on pancreatic lymphatics in nonobese diabetic mouse with prevention of insulitis and diabetes by adjuvant immunotherapy. 1538 76

During mammalian vascular development, endothelial cells form a complex array of vessels that differ markedly in structure and function, but the molecular basis for this vascular complexity is poorly understood. Recent insights into endothelial diversity have come from the identification of molecular markers expressed on distinct endothelial cell populations. One such marker, the PAL-E antibody, has been used for almost 20 years to distinguish blood and lymphatic vessels, but the identity of the protein recognized by PAL-E has been unknown. In the present study we have used protein purification and tandem mass spectrometry analysis of tryptic peptides to identify the PAL-E antigen as a secreted form of vimentin. Vimentin has been well characterized as an intracellular intermediate filament protein expressed broadly in mesenchymal cells. In contrast, PAL-E-reactive vimentin is secreted extracellularly, its synthesis is restricted to a distinct population of blood endothelial cells and activated macrophages, and PAL-E-reactive vimentin is found in circulating human blood. PAL-E-reactive vimentin does not arise from an endothelial cell-specific mRNA transcript but is the product of cell-specific posttranslational modification. The PAL-E antibody therefore defines secretion of vimentin as a molecular distinction among endothelial cells and exposes a novel, extracellular role for vimentin in the blood vasculature.
Mol Cell Biol 2004 Oct
PMID:The endothelial cell-specific antibody PAL-E identifies a secreted form of vimentin in the blood vasculature. 1545 90

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.
Mol Cell Biol 2005 Mar
PMID:Vascular endothelial growth factor D is dispensable for development of the lymphatic system. 1574 36

Reelin, a glycoprotein secreted by Cajal-Retzius cells, is crucial for cortex lamination and cell positioning. Some peripheral reelin expression has also been reported. Here we describe in developing rat and human and in adult rat very definite reelin immunolocalization in two cell types. Reelin was present in endothelial cells of lymphatic vessels, but not of blood vessels. Reelin was also detected in stellate (Ito) cells of the liver as shown by immunoelectron microscopic examination. The immunlocalization observed in adult tissues indicates a broader role of reelin beyond its previously demonstrated role in neuronal development.
Anat Rec A Discov Mol Cell Evol Biol 2005 Jul
PMID:Reelin immunoreactivity in lymphatics and liver during development and adult life. 1591 22

Lymphangiogenesis is key to the lymphatic spread of cancer cells. The current study examined the potential effect of hepatocyte growth factor (HGF), a factor known to have strong biological effects on endothelial cells, on the lymphangiogenic function of endothelial cells and the formation of lymphatic vessels using both in vitro and in vivo models. Human endothelial cells that have lymphatic characteristics, human prostate and breast cancer cells PC-3 and MDA MB 231, were used. Expression of lymphatic markers, podoplanin, Prox-1, vascular endothelial growth factor receptor 3 (VEGF-R3) and LYVE-1 was determined using reverse transcription polymerase reaction and quantitative PCR. In nude mice prostate and breast xenograft tumour models, either HGF or an HGF-producing fibroblast cell line MRC-5 was given with or without the HGF antagonist, NK4. The lymphangiogenic marker and lymphatic vessels in tumour tissues were also assessed using quantitative PCR and immunohistochemistry, respectively. In the mice tumour models, infusion of rhHGF significantly increased the levels of podoplanin and LYVE-1 in the tumour (p=0.05 for podoplanin and p<0.05 for LYVE-1 vs. without HGF in the prostate tumour model, p<0.05 for podoplanin and p<0.01 for LYVE-1 vs. without HGF for the breast tumour model; p<0.05 for podoplanin and p<0.01 for LYVE-1 vs. without HGF in the breast tumour model). The increased level of LYVE-1 transcript was supported by an increase in the number of LYVE-1-positive lymphatic vessels in tumours, using immunohistochemical analysis. Co-injection of MRC5 cells also increased the levels of LYVE-1 and number of LYVE-1-positive vessels in tumour tissues. The effects of HGF and MRC5 were significantly reduced by the HGF antagonist, NK4. In the in vitro models, rhHGF significantly increased the level of both podoplanin and LYVE-1, as shown by quantitative PCR analysis. Hepatocyte growth factor has potential lymphangiogenic activities, and this may have important implications in the nodal spread of cancer cells.
Int J Mol Med 2005 Oct
PMID:The potential lymphangiogenic effects of hepatocyte growth factor/scatter factor in vitro and in vivo. 1614 11

Fibroblast growth factors play important roles in angiogenesis, but their functions in lymphangiogenesis remain poorly understood. The homeodomain transcription factor Prox1 is essential for development of the lymphatic system by specifying lymphatic endothelial cell (LEC) fate. Here, we identify fibroblast growth factor (FGF) receptor (FGFR)-3 as a novel Prox1 target gene. Ectopic overexpression of Prox1 in blood vascular endothelial cells up-regulates FGFR-3. Prox1 induces the expression of the IIIc isoform, which we also found to be the major isoform of FGFR-3 expressed in LECs. This transcriptional activation is mediated by a direct binding of Prox1 to newly identified Prox1-response elements in the FGFR-3 promoter. Consistently, FGFR-3 is up-regulated in Prox1-positive newly formed lymphatic vessels during embryogenesis and its lymphatic-specific expression is maintained throughout development. We also found that FGF-1 and FGF-2 promote proliferation, migration, and survival of cultured LECs without involvement of vascular endothelial cell growth factor receptor-3. We show that FGF-2 binds to low- and high-affinity receptors on LECs and is efficiently internalized and processed. Moreover, functional inhibition of FGFR-3 using small interfering RNA represses LEC proliferation. Together, these results indicate that FGFR-3 is an initial target of Prox1 during the lymphatic cell fate specification and that FGF signaling may play an important role in lymphatic vessel development.
Mol Biol Cell 2006 Feb
PMID:Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. 1629 64

The development of functional blood and lymphatic vessels requires spatio-temporal coordination of the production and release of growth factors such as vascular endothelial growth factors (VEGFs). VEGF family proteins are produced in multiple isoforms with distinct biological properties and bind to three types of VEGF receptors. A VEGF-A splice variant, VEGF-A(165)b, has recently been isolated from kidney epithelial cells. This variant is identical to VEGF-A(165) except for the last six amino acids encoded by an alternative exon. VEGF-A(165)b and VEGF-A(165) bind VEGF receptors 1 and 2 with similar affinity. VEGF-A(165)b elicits drastically reduced activity in angiogenesis assays and even counteracts signaling by VEGF-A(165). VEGF-A(165)b weakly binds to heparan sulfate and does not interact with neuropilin-1, a coreceptor for VEGF receptor 2. To determine the molecular basis for altered signaling by VEGF-A(165)b we measured VEGF receptor 2 and ERK kinase activity in endothelial cells in culture. VEGF-A(165) induced strong and sustained activation of VEGF receptor 2 and ERK-1 and -2, while activation by VEGF-A(165)b was only weak and transient. Taken together these data show that VEGF-A(165)b has attenuated signaling potential through VEGF receptor 2 defining this new member of the VEGF family as a partial receptor agonist.
Cell Mol Life Sci 2006 Sep
PMID:A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. 1690 99

The hyaluronan receptor LYVE-1 is expressed abundantly on the surfaces of lymphatic vessels and lymph node sinus endothelial cells from early development, where it has been suggested to function both in cell adhesion/transmigration and as a scavenger for hyaluronan turnover. To investigate the physiological role(s) of LYVE-1, we generated mice in which the gene for the receptor was inactivated by replacement with a beta-galactosidase reporter. LYVE-1(-/-) mice displayed an apparently normal phenotype, with no obvious alteration in lymphatic vessel ultrastructure or function and no apparent change in secondary lymphoid tissue structure or cellularity. In addition, the levels of hyaluronan in tissue and blood were unchanged. LYVE-1(-/-) mice also displayed normal trafficking of cutaneous CD11c(+) dendritic cells to draining lymph nodes via afferent lymphatics and normal resolution of oxazolone-induced skin inflammation. Finally, LYVE-1(-/-) mice supported normal growth of transplanted B16F10 melanomas and Lewis lung carcinomas. These results indicate that LYVE-1 is not obligatory for normal lymphatic development and function and suggest either the existence of compensatory receptors or a role more specific than that previously envisaged.
Mol Cell Biol 2007 Jan
PMID:Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. 1710 72

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.
Mol Cell Biol 2007 Jun
PMID:Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. 1743 36

Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system.
Cell Mol Life Sci 2007 Aug
PMID:Molecular mechanisms of lymphatic vascular development. 1745 98


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