TY - JOUR T1 - Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis JF - PLoS ONE Y1 - 2010 A1 - Albrecht, Imke A1 - Kopfstein, Lucie A1 - Strittmatter, Karin A1 - Schomber, Tibor A1 - Falkevall, Annelie A1 - Hagberg, Carolina E A1 - Lorentz, Pascal A1 - Jeltsch, Michael A1 - Alitalo, Kari A1 - Eriksson, Ulf A1 - Christofori, Gerhard A1 - Pietras, Kristian AB - BACKGROUND: The family of vascular endothelial growth factors (VEGF) contains key regulators of blood and lymph vessel development, including VEGF-A, -B, -C, -D, and placental growth factor. The role of VEGF-B during physiological or pathological angiogenesis has not yet been conclusively delineated. Herein, we investigate the function of VEGF-B by the generation of mouse models of cancer with transgenic expression of VEGF-B or homozygous deletion of Vegfb. METHODOLOGY/PRINCIPAL FINDINGS: Ectopic expression of VEGF-B in the insulin-producing β-cells of the pancreas did not alter the abundance or architecture of the islets of Langerhans. The vasculature from transgenic mice exhibited a dilated morphology, but was of similar density as that of wildtype mice. Unexpectedly, we found that transgenic expression of VEGF-B in the RIP1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis retarded tumor growth. Conversely, RIP1-Tag2 mice deficient for Vegfb presented with larger tumors. No differences in vascular density, perfusion or immune cell infiltration upon altered Vegfb gene dosage were noted. However, VEGF-B acted to increase blood vessel diameter both in normal pancreatic islets and in RIP1-Tag2 tumors. CONCLUSIONS/SIGNIFICANCE: Taken together, our results illustrate the differences in biological function between members of the VEGF family, and highlight the necessity of in-depth functional studies of VEGF-B to fully understand the effects of VEGFR-1 inhibitors currently used in the clinic. VL - 5 UR - http://view.ncbi.nlm.nih.gov/pubmed/21124841 IS - 11 JO - PLoS ONE ER - TY - JOUR T1 - Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium JF - Arterioscler Thromb Vasc Biol Y1 - 2008 A1 - Li, Xuri A1 - Tjwa, Marc A1 - Van Hove, Inge A1 - Enholm, Berndt A1 - Neven, Elke A1 - Paavonen, Karri A1 - Jeltsch, Michael A1 - Juan, Toni Diez A1 - Sievers, Richard E A1 - Chorianopoulos, Emmanuel A1 - Wada, Hiromichi A1 - Vanwildemeersch, Maarten A1 - Noel, Agnes A1 - Foidart, Jean-Michel A1 - Springer, Matthew L A1 - von Degenfeld, Georges A1 - Dewerchin, Mieke A1 - Blau, Helen M A1 - Alitalo, Kari A1 - Eriksson, Ulf A1 - Carmeliet, Peter A1 - Moons, Lieve AB - OBJECTIVE: The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear. METHODS AND RESULTS: We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B(-/-)) or overexpressing VEGF-B(167). After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B(167) overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B(167) overexpression failed to enhance vascular growth in the skin or ischemic limb. CONCLUSIONS: VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities. VL - 28 UR - http://view.ncbi.nlm.nih.gov/pubmed/18511699 IS - 9 JO - Arteriosclerosis, Thrombosis, and Vascular Biology ER - TY - JOUR T1 - Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes JF - FASEB J Y1 - 2002 A1 - Saaristo, Anne A1 - Veikkola, Tanja A1 - Enholm, Berndt A1 - Hytönen, Maija A1 - Arola, Johanna A1 - Pajusola, Katri A1 - Turunen, Païvi A1 - Jeltsch, Michael A1 - Karkkainen, Marika J A1 - Kerjaschki, Dontscho A1 - Bueler, Hansruedi A1 - Ylä-Herttuala, Seppo A1 - Alitalo, Kari AB - Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with hereditary lymphedema. However, VEGF-C can have potent effects on blood vessels because its receptor VEGFR-3 is expressed in certain blood vessels and because the fully processed form of VEGF-C also binds to the VEGFR-2 of blood vessels. To characterize the in vivo effects of VEGF-C on blood and lymphatic vessels, we have overexpressed VEGF-C via adenovirus- and adeno-associated virus-mediated transfection in the skin and respiratory tract of athymic nude mice. This resulted in dose-dependent enlargement and tortuosity of veins, which, along with the collecting lymphatic vessels were found to express VEGFR-2. Expression of angiopoietin 1 blocked the increased leakiness of the blood vessels induced by VEGF-C whereas vessel enlargement and lymphangiogenesis were not affected. However, angiogenic sprouting of new blood vessels was not observed in response to AdVEGF-C or AAV-VEGF-C. These results show that virally produced VEGF-C induces blood vessel changes, including vascular leak, but its angiogenic potency is much reduced compared with VEGF in normal skin. VL - 16 UR - http://view.ncbi.nlm.nih.gov/pubmed/12087065 IS - 9 JO - The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology ER - TY - JOUR T1 - Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin JF - Circ Res Y1 - 2001 A1 - Enholm, B A1 - Karpanen, T A1 - Jeltsch, M A1 - Kubo, H A1 - Stenback, F A1 - Prevo, R A1 - Jackson, D G A1 - Yla-Herttuala, S A1 - Alitalo, K AB - The 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. VL - 88 UR - http://view.ncbi.nlm.nih.gov/pubmed/11282897 IS - 6 JO - Circulation Research ER - TY - JOUR T1 - Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta JF - Circulation Y1 - 2000 A1 - Hiltunen, M O A1 - Laitinen, M A1 - Turunen, M P A1 - Jeltsch, M A1 - Hartikainen, J A1 - Rissanen, T T A1 - Laukkanen, J A1 - Niemi, M A1 - Kossila, M A1 - Häkkinen, T P A1 - Kivelä, A A1 - Enholm, B A1 - Mansukoski, H A1 - Turunen, A M A1 - Alitalo, K A1 - Ylä-Herttuala, S AB - BACKGROUND: 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. VL - 102 UR - http://view.ncbi.nlm.nih.gov/pubmed/11056103 IS - 18 JO - Circulation ER - TY - JOUR T1 - Current biology of VEGF-B and VEGF-C JF - Curr Opin Biotechnol Y1 - 1999 A1 - Olofsson, B A1 - Jeltsch, M A1 - Eriksson, U A1 - Alitalo, K AB - Endothelial 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. VL - 10 UR - http://view.ncbi.nlm.nih.gov/pubmed/10600689 IS - 6 JO - Current Opinion in Biotechnology ER - TY - JOUR T1 - Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells JF - Proc Natl Acad Sci U S A Y1 - 1998 A1 - Olofsson, B A1 - Korpelainen, E A1 - Pepper, M S A1 - Mandriota, S J A1 - Aase, K A1 - Kumar, V A1 - Gunji, Y A1 - Jeltsch, M M A1 - Shibuya, M A1 - Alitalo, K A1 - Eriksson, U AB - The 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. VL - 95 UR - http://view.ncbi.nlm.nih.gov/pubmed/9751730 IS - 20 JO - Proceedings of the National Academy of Sciences of the United States of America ER - TY - JOUR T1 - Vascular endothelial growth factors VEGF-B and VEGF-C JF - J Cell Physiol Y1 - 1997 A1 - Joukov, V A1 - Kaipainen, A A1 - Jeltsch, M A1 - Pajusola, K A1 - Olofsson, B A1 - Kumar, V A1 - Eriksson, U A1 - Alitalo, K VL - 173 UR - http://view.ncbi.nlm.nih.gov/pubmed/9365524 IS - 2 JO - Journal of Cellular Physiology ER -