title: Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes.
abstract: 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.
authors.affiliation: Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum, University of Helsinki and Helsinki University Central Hospital, 00014 Helsinki, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Saaristo
authors.forename: Tanja
authors.initials: T
authors.lastname: Veikkola
authors.forename: Berndt
authors.initials: B
authors.lastname: Enholm
authors.forename: Maija
authors.initials: M
authors.lastname: Hytönen
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.forename: Katri
authors.initials: K
authors.lastname: Pajusola
authors.forename: Païvi
authors.initials: P
authors.lastname: Turunen
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.forename: Marika J
authors.initials: MJ
authors.lastname: Karkkainen
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Bueler
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D042683:Angiopoietin-1; D000818:Animals; D001808:Blood Vessels / Q000033:anatomy & histology / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D005822:Genetic Vectors; D008208:Lymphatic System / Q000254:growth & development; D008222:Lymphokines / Q000235:genetics; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009297:Nasal Mucosa / Q000098:blood supply; D018919:Neovascularization, Physiologic; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D012867:Skin / Q000098:blood supply* / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042442:Vascular Endothelial Growth Factors
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor