01922nas a2200253   4500008004100000245014100041210006900182260001400251300001500265490000700280520116200287100001601449700001901465700001601484700001901500700001201519700001301531700001301544700001701557700001501574700001501589700001601604856004801620       1998                        eng d00aVascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells0 aVascular endothelial growth factor B VEGFB binds to VEGF recepto  c1998/Sep/  a11709 - 140 v953 aThe vascular endothelial growth factor (VEGF) family has recently expanded by the identification and cloning of three additional members, namely VEGF-B, VEGF-C, and VEGF-D. In this study we demonstrate that VEGF-B binds selectively to VEGF receptor-1/Flt-1. This binding can be blocked by excess VEGF, indicating that the interaction sites on the receptor are at least partially overlapping. Mutating the putative VEGF receptor-1/Flt-1 binding determinants Asp63, Asp64, and Glu67 to alanine residues in VEGF-B reduced the affinity to VEGF receptor-1 but did not abolish binding. Mutational analysis of conserved cysteines contributing to VEGF-B dimer formation suggest a structural conservation with VEGF and platelet-derived growth factor. Proteolytic processing of the 60-kDa VEGF-B186 dimer results in a 34-kDa dimer containing the receptor-binding epitopes. The binding of VEGF-B to its receptor on endothelial cells leads to increased expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1, suggesting a role for VEGF-B in the regulation of extracellular matrix degradation, cell adhesion, and migration.1 aOlofsson, B1 aKorpelainen, E1 aPepper, M S1 aMandriota, S J1 aAase, K1 aKumar, V1 aGunji, Y1 aJeltsch, M M1 aShibuya, M1 aAlitalo, K1 aEriksson, U  uhttp://view.ncbi.nlm.nih.gov/pubmed/975173002306nas 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/980815201810nas 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/9365524