02115nas a2200133   4500008004100000020001300041245007300054210006900127260001600196300001200212490000800224520168300232856006601915       2018                        eng d  a0940960200aKey molecules in lymphatic development, function, and identification0 aKey molecules in lymphatic development function and identificati  c2018/09/01/  a25 - 340 v2193 aWhile both blood and lymphatic vessels transport fluids and thus share many similarities, they also show functional and structural differences, which can be used to differentiate them. Specific visualization of lymphatic vessels has historically been and still is a pivot point in lymphatic research. Many of the proteins that are investigated by molecular biologists in lymphatic research have been defined as marker molecules, i.e. to visualize and distinguish lymphatic endothelial cells (LECs) from other cell types, most notably from blood vascular endothelial cells (BECs) and cells of the hematopoietic lineage.Among the factors that drive the developmental differentiation of lymphatic structures from venous endothelium, Prospero homeobox protein 1 (PROX1) is the master transcriptional regulator. PROX1 maintains lymphatic identity also in the adult organism and thus is a universal LEC marker. Vascular endothelial growth factor receptor-3 (VEGFR-3) is the major tyrosine kinase receptor that drives LEC proliferation and migration. The major activator for VEGFR-3 is vascular endothelial growth factor-C (VEGF-C). However, before VEGF-C can signal, it needs to be proteolytically activated by an extracellular protein complex comprised of Collagen and calcium binding EGF domains 1 (CCBE1) protein and the protease A disintegrin and metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3).This minireview attempts to give an overview of these and a few other central proteins that scientific inquiry has linked specifically to the lymphatic vasculature. It is limited in scope to a brief description of their main functions, properties and developmental roles.  uhttp://linkinghub.elsevier.com/retrieve/pii/S094096021830071200532nas a2200097   4500008004100000245007900041210006900120260007600189520012600265856004300391       2014                        eng d00aFrom molecular biology to a causal treatment of lymphatic system disorders0 aFrom molecular biology to a causal treatment of lymphatic system  aHalle (Saale), GermanybDeutsche Gesellschaft für Lymphologiec10/20143 a<a href="http://www.dglymph.de/fileadmin/global/pdfs/LymphForsch_02-14.pdf">Original Conference Abstracts (in German)</a>  uhttps://jeltsch.org/abstract-Halle201400667nas a2200217   4500008004100000245010700041210006900148260001100217300001600228490000700244100001300251700001700264700001700281700001500298700001600313700002200329700001700351700001700368700001800385856004600403       2011                        eng d00aVEGF-C/VEGFR-3 Signaling Regulates Inflammatory Response in Development of Obliterative Airway Disease0 aVEGFCVEGFR3 Signaling Regulates Inflammatory Response in Develop  c2011//  aS118 - S1180 v301 aKrebs, R1 aTikkanen, JM1 aRopponen, JO1 aJeltsch, M1 aJokinen, JJ1 aYlä-Herttuala, S1 aKoskinen, PK1 aNykänen, AI1 aLemström, KB  uhttps://jeltsch.org/Krebs2011?language=hu01909nas a2200229   4500008004100000245010400041210006900145260001400214300001200228490000700240520124400247100001401491700001601505700001501521700001201536700001601548700001301564700001701577700002101594700001501615856004901630       2001                        eng d00aAdenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin0 aAdenoviral expression of vascular endothelial growth factorC ind  c2001/Mar/  a623 - 90 v883 aThe growth of blood and lymphatic vasculature is mediated in part by secreted polypeptides of the vascular endothelial growth factor (VEGF) family. The prototype VEGF binds VEGF receptor (VEGFR)-1 and VEGFR-2 and is angiogenic, whereas VEGF-C, which binds to VEGFR-2 and VEGFR-3, is either angiogenic or lymphangiogenic in different assays. We used an adenoviral gene transfer approach to compare the effects of these growth factors in adult mice. Recombinant adenoviruses encoding human VEGF-C or VEGF were injected subcutaneously into C57Bl6 mice or into the ears of nude mice. Immunohistochemical analysis showed that VEGF-C upregulated VEGFR-2 and VEGFR-3 expression and VEGF upregulated VEGFR-2 expression at 4 days after injection. After 2 weeks, histochemical and immunohistochemical analysis, including staining for the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), the vascular endothelial marker platelet-endothelial cell adhesion molecule-1 (PECAM-1), and the proliferating cell nuclear antigen (PCNA) revealed that VEGF-C induced mainly lymphangiogenesis in contrast to VEGF, which induced only angiogenesis. These results have significant implications in the planning of gene therapy using these growth factors.1 aEnholm, B1 aKarpanen, T1 aJeltsch, M1 aKubo, H1 aStenback, F1 aPrevo, R1 aJackson, D G1 aYla-Herttuala, S1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/1128289701998nas a2200265   4500008004100000245012000041210006900161260001400230300001400244490000700258520123100265100001601496700001501512700001501527700001601542700001501558700001701573700001201590700001601602700001801618700001501636700001701651700001501668856004901683       2001                        eng d00aSignalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice0 aSignalling via vascular endothelial growth factor receptor3 is s  c2001/Mar/  a1223 - 310 v203 aVascular endothelial growth factor receptor-3 (VEGFR-3) has an essential role in the development of embryonic blood vessels; however, after midgestation its expression becomes restricted mainly to the developing lymphatic vessels. The VEGFR-3 ligand VEGF-C stimulates lymphangiogenesis in transgenic mice and in chick chorioallantoic membrane. As VEGF-C also binds VEGFR-2, which is expressed in lymphatic endothelia, it is not clear which receptors are responsible for the lymphangiogenic effects of VEGF-C. VEGF-D, which binds to the same receptors, has been reported to induce angiogenesis, but its lymphangiogenic potential is not known. In order to define the lymphangiogenic signalling pathway we have created transgenic mice overexpressing a VEGFR-3-specific mutant of VEGF-C (VEGF-C156S) or VEGF-D in epidermal keratinocytes under the keratin 14 promoter. Both transgenes induced the growth of lymphatic vessels in the skin, whereas the blood vessel architecture was not affected. Evidence was also obtained that these growth factors act in a paracrine manner in vivo. These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo.1 aVeikkola, T1 aJussila, L1 aMakinen, T1 aKarpanen, T1 aJeltsch, M1 aPetrova, T V1 aKubo, H1 aThurston, G1 aMcDonald, D M1 aAchen, M G1 aStacker, S A1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/1125088902021nas a2200289   4500008004100000245009500041210006900136260001400205300001300219490000700232520122500239100001901464700001501483700001501498700001601513700001501529700001301544700001501557700001401572700001701586700001701603700001201620700001501632700001901647700001601666856004901682       2001                        eng d00aVascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis0 aVascular endothelial growth factorCmediated lymphangiogenesis pr  c2001/Feb/  a672 - 820 v203 aMetastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor-C (VEGF-C) is a recently described lymphangiogenic factor. Increased expression of VEGF-C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF-C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF-C expression, driven by the rat insulin promoter (Rip), is targeted to beta-cells of the endocrine pancreas. In contrast to wild-type mice, which lack peri-insular lymphatics, RipVEGF-C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic beta-cell tumours that are neither lymphangiogenic nor metastatic. Double-transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of beta-cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.1 aMandriota, S J1 aJussila, L1 aJeltsch, M1 aCompagni, A1 aBaetens, D1 aPrevo, R1 aBanerji, S1 aHuarte, J1 aMontesano, R1 aJackson, D G1 aOrci, L1 aAlitalo, K1 aChristofori, G1 aPepper, M S  uhttp://view.ncbi.nlm.nih.gov/pubmed/1117921202694nas a2200313   4500008004100000245011900041210006900160260001400229300001300243490000800256520179900264100001802063700001602081700001702097700001502114700001902129700001802148700001702166700001302183700001502196700001902211700001502230700001402245700001802259700001702277700001502294700002202309856004902331       2000                        eng d00aIntravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta0 aIntravascular adenovirusmediated VEGFC gene transfer reduces neo  c2000/Oct/  a2262 - 80 v1023 aBACKGROUND: Gene transfer to the vessel wall may provide new possibilities for the treatment of vascular disorders, such as postangioplasty restenosis. In this study, we analyzed the effects of adenovirus-mediated vascular endothelial growth factor (VEGF)-C gene transfer on neointima formation after endothelial denudation in rabbits. For comparison, a second group was treated with VEGF-A adenovirus and a third group with lacZ adenovirus. Clinical-grade adenoviruses were used for the study. METHODS AND RESULTS: Aortas of cholesterol-fed New Zealand White rabbits were balloon-denuded, and gene transfer was performed 3 days later. Animals were euthanized 2 and 4 weeks after the gene transfer, and intima/media ratio (I/M), histology, and cell proliferation were analyzed. Two weeks after the gene transfer, I/M in the lacZ-transfected control group was 0. 57+/-0.04. VEGF-C gene transfer reduced I/M to 0.38+/-0.02 (P:<0.05 versus lacZ group). I/M in VEGF-A-treated animals was 0.49+/-0.17 (P:=NS). The tendency that both VEGF groups had smaller I/M persisted at the 4-week time point, when the lacZ group had an I/M of 0.73+/-0.16, the VEGF-C group 0.44+/-0.14, and the VEGF-A group 0. 63+/-0.21 (P:=NS). Expression of VEGF receptors 1, 2, and 3 was detected in the vessel wall by immunocytochemistry and in situ hybridization. As an additional control, the effect of adenovirus on cell proliferation was analyzed by performing gene transfer to intact aorta without endothelial denudation. No differences were seen in smooth muscle cell proliferation or I/M between lacZ adenovirus and 0.9% saline-treated animals. CONCLUSIONS: Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations.1 aHiltunen, M O1 aLaitinen, M1 aTurunen, M P1 aJeltsch, M1 aHartikainen, J1 aRissanen, T T1 aLaukkanen, J1 aNiemi, M1 aKossila, M1 aHäkkinen, T P1 aKivelä, A1 aEnholm, B1 aMansukoski, H1 aTurunen, A M1 aAlitalo, K1 aYlä-Herttuala, S  uhttp://view.ncbi.nlm.nih.gov/pubmed/1105610300881nas a2200169   4500008004100000245004100041210003900082260001400121300001300135490000700148520044500155100001600600700001500616700001600631700001500647856004900662       1999                        eng d00aCurrent biology of VEGF-B and VEGF-C0 aCurrent biology of VEGFB and VEGFC  c1999/Dec/  a528 - 350 v103 aEndothelial growth factors and their receptors may provide important therapeutic tools for the treatment of pathological conditions characterised by defective or aberrant angiogenesis. Vascular endothelial growth factor (VEGF) is pivotal for vasculogenesis and for angiogenesis in normal and pathological conditions. VEGF-B and VEGF-C provide this gene family with additional functions, for example, VEGF-C also regulates lymphangiogenesis.1 aOlofsson, B1 aJeltsch, M1 aEriksson, U1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/1060068901686nas a2200217   4500008004100000245013700041210006900178260001400247300001300261490000700274520102000281100001501301700001501316700001201331700001601343700001401359700001501373700001501388700001701403856004801420       1998                        eng d00aVascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)0 aVascular endothelial growth factor D VEGFD is a ligand for the t  c1998/Jan/  a548 - 530 v953 aWe have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.1 aAchen, M G1 aJeltsch, M1 aKukk, E1 aMäkinen, T1 aVitali, A1 aWilks, A F1 aAlitalo, K1 aStacker, S A  uhttp://view.ncbi.nlm.nih.gov/pubmed/943522902306nas a2200181   4500008004100000245020900041210006900250260001400319300001300333490000800346520164400354100001601998700001902014700001502033700001302048700001502061856004802076       1998                        eng d00aVascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity0 aVascular endothelial growth factor VEGFC synergizes with basic f  c1998/Dec/  a439 - 520 v1773 aVascular endothelial growth factor-C (VEGF-C) is a recently characterized member of the VEGF family of angiogenic polypeptides. We demonstrate here that VEGF-C is angiogenic in vitro when added to bovine aortic or lymphatic endothelial (BAE and BLE) cells but has little or no effect on bovine microvascular endothelial (BME) cells. As reported previously for VEGF, VEGF-C and basic fibroblast growth factor (bFGF) induced a synergistic in vitro angiogenic response in all three cells lines. Unexpectedly, VEGF and VEGF-C also synergized in the in vitro angiogenic response when assessed on BAE cells. Characterization of VEGF receptor (VEGFR) expression revealed that BME, BAE, and BLE cell lines express VEGFR-1 and -2, whereas of the three cell lines assessed, only BAE cells express VEGFR-3. We also demonstrate that VEGF-C increases plasminogen activator (PA) activity in the three bovine endothelial cell lines and that this is accompanied by a concomitant increase in PA inhibitor-1. Addition of alpha2-antiplasmin to BME cells co-treated with bFGF and VEGF-C partially inhibited collagen gel invasion. These results demonstrate, first, that by acting in concert with bFGF or VEGF, VEGF-C has a potent synergistic effect on the induction of angiogenesis in vitro and, second, that like VEGF and bFGF, VEGF-C is capable of altering endothelial cell extracellular proteolytic activity. These observations also highlight the notion of context, i.e., that the activity of an angiogenesis-regulating cytokine depends on the presence and concentration of other cytokines in the pericellular environment of the responding endothelial cell.1 aPepper, M S1 aMandriota, S J1 aJeltsch, M1 aKumar, V1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/980815201905nas a2200217   4500008004100000245009100041210006900132260001400201300001500215490000800230520128700238100001401525700001201539700001301551700001501564700001601579700001501595700001401610700001501624856004801639       1997                        eng d00aGenomic organization of human and mouse genes for vascular endothelial growth factor C0 aGenomic organization of human and mouse genes for vascular endot  c1997/Oct/  a25176 - 830 v2723 aWe report here the cloning and characterization of human and mouse genes for vascular endothelial growth factor C (VEGF-C), a newly isolated member of the vascular endothelial growth factor/platelet-derived growth factor (VEGF/PDGF) family. Both VEGF-C genes comprise over 40 kilobase pairs of genomic DNA and consist of seven exons, all containing coding sequences. The VEGF homology domain of VEGF-C is encoded by exons 3 and 4. Exons 5 and 7 encode cysteine-rich motifs of the type C6C10CRC, and exon 6 encodes additional C10CXCXC motifs typical of a silk protein. A putative alternatively spliced rare RNA form lacking exon 4 was identified in human fibrosarcoma cells, and a major transcription start site was located in the human VEGF-C gene 523 base pairs upstream of the translation initiation codon. The upstream promoter sequences contain conserved putative binding sites for Sp-1, AP-2, and NF-kappaB transcription factors but no TATA box, and they show promoter activity when transfected into cells. The VEGF-C gene structure is thus assembled from exons encoding propeptides and distinct cysteine-rich domains in addition to the VEGF homology domain, and it shows both similarities and distinct differences in comparison with other members of the VEGF/PDGF gene family.1 aChilov, D1 aKukk, E1 aTaira, S1 aJeltsch, M1 aKaukonen, J1 aPalotie, A1 aJoukov, V1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/931213001376nas a2200241   4500008004100000245006300041210006200104260001400166300001300180490000800193520074000201100001500941700001700956700001400973700001200987700001300999700001501012700001401027700001601041700001401057700001501071856004801086       1997                        eng d00aHyperplasia of lymphatic vessels in VEGF-C transgenic mice0 aHyperplasia of lymphatic vessels in VEGFC transgenic mice  c1997/May/  a1423 - 50 v2763 aNo growth factors specific for the lymphatic vascular system have yet been described. Vascular endothelial growth factor (VEGF) regulates vascular permeability and angiogenesis, but does not promote lymphangiogenesis. Overexpression of VEGF-C, a ligand of the VEGF receptors VEGFR-3 and VEGFR-2, in the skin of transgenic mice resulted in lymphatic, but not vascular, endothelial proliferation and vessel enlargement. Thus, VEGF-C induces selective hyperplasia of the lymphatic vasculature, which is involved in the draining of interstitial fluid and in immune function, inflammation, and tumor metastasis. VEGF-C may play a role in disorders involving the lymphatic system and may be of potential use in therapeutic lymphangiogenesis.1 aJeltsch, M1 aKaipainen, A1 aJoukov, V1 aMeng, X1 aLakso, M1 aRauvala, H1 aSwartz, M1 aFukumura, D1 aJain, R K1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/916201101810nas a2200229   4500008004100000245008100041210006900122260001400191300001500205490000700220520117000227100001401397700001301411700001301424700001501437700002201452700001101474700001501485700001701500700001501517856004801532       1997                        eng d00aProteolytic processing regulates receptor specificity and activity of VEGF-C0 aProteolytic processing regulates receptor specificity and activi  c1997/Jul/  a3898 - 9110 v163 aThe recently identified vascular endothelial growth factor C (VEGF-C) belongs to the platelet-derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the endothelial-specific receptor tyrosine kinases VEGFR-3 and VEGFR-2. The VEGF homology domain spans only about one-third of the cysteine-rich VEGF-C precursor. Here we have analysed the role of post-translational processing in VEGF-C secretion and function, as well as the structure of the mature VEGF-C. The stepwise proteolytic processing of VEGF-C generated several VEGF-C forms with increased activity towards VEGFR-3, but only the fully processed VEGF-C could activate VEGFR-2. Recombinant 'mature' VEGF-C made in yeast bound VEGFR-3 (K[D] = 135 pM) and VEGFR-2 (K[D] = 410 pM) and activated these receptors. Like VEGF, mature VEGF-C increased vascular permeability, as well as the migration and proliferation of endothelial cells. Unlike other members of the PDGF/VEGF family, mature VEGF-C formed mostly non-covalent homodimers. These data implicate proteolytic processing as a regulator of VEGF-C activity, and reveal novel structure-function relationships in the PDGF/VEGF family.1 aJoukov, V1 aSorsa, T1 aKumar, V1 aJeltsch, M1 aClaesson-Welsh, L1 aCao, Y1 aSaksela, O1 aKalkkinen, N1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/923380000565nas a2200205   4500008004100000245005800041210005600099260001400155300001200169490000800181100001400189700001700203700001500220700001600235700001600251700001300267700001600280700001500296856004800311       1997                        eng d00aVascular endothelial growth factors VEGF-B and VEGF-C0 aVascular endothelial growth factors VEGFB and VEGFC  c1997/Nov/  a211 - 50 v1731 aJoukov, V1 aKaipainen, A1 aJeltsch, M1 aPajusola, K1 aOlofsson, B1 aKumar, V1 aEriksson, U1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/936552402083nas a2200205   4500008004100000245011700041210006900158260001400227300001400241490000800255520146100263100001201724700001901736700001301755700001701768700001501785700001401800700001501814856004801829       1996                        eng d00aVEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development0 aVEGFC receptor binding and pattern of expression with VEGFR3 sug  c1996/Dec/  a3829 - 370 v1223 aThe 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.1 aKukk, E1 aLymboussaki, A1 aTaira, S1 aKaipainen, A1 aJeltsch, M1 aJoukov, V1 aAlitalo, K  uhttp://view.ncbi.nlm.nih.gov/pubmed/9012504