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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1547-1548. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Karpanen, T. Articles by Alitalo, K. Search for Related Content PubMed Articles by Karpanen, T. Articles by Alitalo, K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  HEMOSTASIS Comment on Ny et al, page 1740 VEGF-D: a modifier of embryonic lymphangiogenesis Terhi Karpanen, and Kari Alitalo HUBRECHT INSTITUTE; UNIVERSITY OF HELSINKI In this issue of Blood, Ny and colleagues disclose a modifier role for VEGF-D and a critical function for VEGFR-3 in embryonic lymphangiogenesis in Xenopus tadpoles. VEGF-D potently stimulates lymphangiogenesis in adults and promotes metastasis of both human and experimental mouse tumors.1–4 However, studies in gene-deficient mice have suggested that it is dispensable for embryonic lymphatic vascular development.5 Ny et al now show that VEGF-D functions as a modifier of VEGF-C–driven early sprouting and migration of lymphatic endothelial cells in developing frog embryos and demonstrate the critical role of their receptor VEGFR-3 in this process. Stimulation or inhibition of lymphangiogenesis, especially via the VEGF-C/VEGF-D/VEGFR-3 pathway, has proven beneficial in preclinical models of lymphedema and tumor metastasis, respectively, but their application to the treatment of human disease requires more detailed understanding of the molecular basis of lymphangiogenesis. Genetic studies in mice have revealed the importance of several key players in this process but many important issues remain to be resolved. Recently, the characterization of a lymphatic vascular system in zebrafish and the analysis of lymphatic vessel development in frog embryos have made these small organisms models of choice for genetic and chemical screens for regulators of lymphatic vascular development as well as for in vivo imaging of lymphangiogenic processes. Ny et al employ genetic down regulation in Xenopus tadpoles to demonstrate the subtle transient role of VEGF-D and its cooperation with VEGF-C in embryonic lymphangiogenesis. View larger version (57K): [in this window] [in a new window]   VEGF-C is essential for embryonic lymphatic vascular development whereas VEGF-D has a dispensable modifier role in this process. Nevertheless, both growth factors potently stimulate lymphangiogenesis in adults. VEGFR-3 is required for the remodeling of the primary blood vascular plexus in midgestation mouse embryos, apparently in a VEGF-C/VEGF-D independent manner.7 Later in embryogenesis, VEGFR-3 becomes restricted to lymphatic vessels and is critical for embryonic lymphangiogenesis and postnatal lymphatic vessel survival. At least in adult lymphangiogenesis, VEGFR-3 can cooperate with the major angiogenic receptor, VEGFR-2. ? indicates possible additional ligand or interaction.   VEGF-C and VEGF-D have similar domain structure, both undergo proteolytic processing in a similar manner and, in humans, both share the same receptor-binding specificity. Mouse VEGF-D differs from its human counterpart and from VEGF-C in that it does not bind to the major angiogenic receptor VEGFR-2, which has been shown to cooperate with VEGFR-3 in lymphatic endothelial cell migration and proliferation. Whereas VEGF-C is essential in mouse lymphatic vascular development, it remains to be resolved to what extent the lack of VEGFR-2 binding accounts for the dispensable role of VEGF-D in this process.5,6 Elucidation of the receptor-binding pattern of Xenopus VEGF-D and finding whether it explains the functional difference between VEGF-C and VEGF-D in this organism might bring us a step forward in solving this question. A hint to the lymphangiogenic modifier role of VEGF-D is provided by the fact that exogenous VEGF-D protein administration is able to partially rescue the impaired sprouting and migration of lymphatic endothelial cells in VEGF-C–deficient mouse embryos,6 although loss of endogenous VEGF-D does not aggravate the VEGF-C null phenotype.7 Death of VEGFR-3–deficient mice due to blood vascular defects prior to lymphatic vessel development has precluded studies of the role of VEGFR-3 in mouse embryonic lymphangiogenesis.8 The importance of VEGFR-3 signaling in embryonic lymphatic vascular development, postnatal lymphatic vessel survival, and stimulation of adult lymphangiogenesis has been directly or indirectly demonstrated in various experimental settings in several species. By using genetic down-regulation and chemical inhibition, Ny et al document the critical role of VEGFR-3 in developmental lymphangiogenesis in the Xenopus tadpole model and thus the functional conservation of VEGFR-3 in this species. A profound understanding of the molecular regulation of lymphatic vascular development and the entire range of functions of its major players and modifiers should enable the development of controlled antilymphangiogenic and prolymphangiogenic therapies. Characterization of the lymphatic system in small model organisms has provided new tools to study lymphangiogenic processes and to complement the methods available in mammals. Ny et al highlight the potential of Xenopus tadpoles in lymphatic vascular research by demonstrating the subtle modifier role of VEGF-D in lymphatic vascular development. Footnotes Conflict-of-interest disclosure: T.K. declares no competing financial interests. K.A. is a minority shareholder of Lymphatix Ltd. and the Chairman of the Scientific Advisory Board of Vegenics Ltd. REFERENCES Veikkola T, Jussila L, Makinen T, et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 2001;20:1223–1231.[CrossRef][Medline] [Order article via Infotrieve] Rissanen TT, Markkanen JE, Gruchala M, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 2003;92:1098–1106.[Abstract/Free Full Text] Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186–191.[CrossRef][Medline] [Order article via Infotrieve] Kopfstein L, Veikkola T, Djonov VG, et al. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol. 2007;170:1348–1361.[Abstract/Free Full Text] Baldwin ME, Halford MM, Roufail S, et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 2005;25:2441–2449.[Abstract/Free Full Text] Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5:74–80.[CrossRef][Medline] [Order article via Infotrieve] Haiko P, Makinen T, Keskitalo S, et al. Deletion of VEGF-C and VEGF-D is not equivalent to VEGFR-3-null in mouse embryos. Mol Cell Biol. 2008;28:4843–4850.[Abstract/Free Full Text] Dumont DJ, Jussila L, Taipale J, et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science. 1998;282:946–949.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Role of VEGF-D and VEGFR-3 in developmental lymphangiogenesis, a chemicogenetic study in Xenopus tadpoles Annelii Ny, Marta Koch, Wouter Vandevelde, Martin Schneider, Christian Fischer, Antonio Diez-Juan, Elke Neven, Ilse Geudens, Sunit Maity, Lieve Moons, Stéphane Plaisance, Diether Lambrechts, Peter Carmeliet, and Mieke Dewerchin Blood 2008 112: 1740-1749. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Karpanen, T. Articles by Alitalo, K. Search for Related Content PubMed Articles by Karpanen, T. Articles by Alitalo, K. 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