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Originally published online as doi:10.2353/ajpath.2008.080378 on November 6, 2008

Published online before print November 6, 2008
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(American Journal of Pathology. 2008;173:1891-1901.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080378

Transgenic Induction of Vascular Endothelial Growth Factor-C Is Strongly Angiogenic in Mouse Embryos but Leads to Persistent Lymphatic Hyperplasia in Adult Tissues

Marja Lohela*, Hanna Heloterä*, Paula Haiko*, Daniel J. Dumont{dagger} and Kari Alitalo*

From the Molecular/Cancer Biology Laboratory,* Department of Pathology, Biomedicum Helsinki, Haartman Institute and Helsinki University Hospital, University of Helsinki, Helsinki, Finland; and the Division of Molecular and Cellular Biology Research,{dagger} Sunnybrook and Women’s Research Institute, Toronto, Canada

Vascular endothelial growth factor-C (VEGF-C) is the quintessential lymphangiogenic growth factor that is required for the development of the lymphatic system and is capable of stimulating lymphangiogenesis in adults by activating its receptor, VEGFR-3. Although VEGF-C is a major candidate molecule for the development of prolymphangiogenic therapy for defective lymphatic vessels in lymphedema, the stability of lymph vessels generated by exogenous VEGF-C administration is not currently known. We studied VEGF-C-stimulated lymphangiogenesis in inducible transgenic mouse models in which growth factor expression can be spatially and temporally controlled without side effects, such as inflammation. VEGF-C induction in adult mouse skin for 1 to 2 weeks caused robust lymphatic hyperplasia that persisted for at least 6 months. VEGF-C induced lymphangiogenesis in numerous tissues and organs when expressed in the vascular endothelium in either neonates or adult mice. Very few or no effects were observed in either blood vessels or collecting lymph vessels. Additionally, VEGF-C stimulated lymphangiogenesis in embryos after the onset of lymphatic vessel development. Strikingly, a strong angiogenic effect was observed after VEGF-C induction in vascular endothelium at any point before embryonic day 16.5. Our results indicate that blood vessels can undergo VEGF-C-induced angiogenesis even after down-regulation of VEGFR-3 in embryos; however, transient VEGF-C expression in adults can induce long-lasting lymphatic hyperplasia with no obvious side effects on the blood vasculature.




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