title: Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation.
abstract: Lymphatic vessel plasticity and stability are of considerable importance when attempting to treat diseases associated with the lymphatic vasculature. Development of lymphatic vessels during embryogenesis is dependent on vascular endothelial growth factor (VEGF)-C but not VEGF-D. Using a recombinant adenovirus encoding a soluble form of their receptor VEGFR-3 (AdVEGFR-3-Ig), we studied lymphatic vessel dependency on VEGF-C and VEGF-D induced VEGFR-3 signaling in postnatal and adult mice. Transduction with AdVEGFR-3-Ig led to regression of lymphatic capillaries and medium-sized lymphatic vessels in mice under 2 weeks of age without affecting collecting lymphatic vessels or the blood vasculature. No effect was observed after this period. The lymphatic capillaries of neonatal mice also regressed partially in response to recombinant VEGFR-3-Ig or blocking antibodies against VEGFR-3, but not to adenovirus-encoded VEGFR-2-Ig. Despite sustained inhibitory VEGFR-3-Ig levels, lymphatic vessel regrowth was observed at 4 weeks of age. Interestingly, whereas transgenic expression of VEGF-C in the skin induced lymphatic hyperplasia even during embryogenesis, similar expression of VEGF-D resulted in lymphangiogenesis predominantly after birth. These results indicate considerable plasticity of lymphatic vessels during the early postnatal period but not thereafter, suggesting that anti-lymphangiogenic therapy can be safely applied in adults.
authors.affiliation: Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, P.O.B. 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Karpanen
authors.forename: Maria
authors.initials: M
authors.lastname: Wirzenius
authors.forename: Taija
authors.initials: T
authors.lastname: Mäkinen
authors.forename: Tanja
authors.initials: T
authors.lastname: Veikkola
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
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; D000818:Animals; D000831:Animals, Newborn; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D008024:Ligands; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D051379:Mice; D012038:Regeneration; D012995:Solubility; D019076:Transgenes; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors; D042643:Vascular Endothelial Growth Factor D / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000097:blood / Q000276:immunology
chemical_list: D006133:Growth Substances; D008024:Ligands; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3