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Molecular and Cellular Biology, August 2008, p. 4843-4850, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.02214-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Deletion of Vascular Endothelial Growth Factor C (VEGF-C) and VEGF-D Is Not Equivalent to VEGF Receptor 3 Deletion in Mouse Embryos

Paula Haiko,¹ Taija Makinen,^1, Salla Keskitalo,¹ Jussi Taipale,^1, Marika J. Karkkainen,¹ Megan E. Baldwin,^2, Steven A. Stacker,² Marc G. Achen,² and Kari Alitalo^1*

Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, Biomedicum Helsinki and Helsinki University Central Hospital, P. O. B. 63 (Haartmaninkatu 8), University of Helsinki, 00014 Helsinki, Finland,¹ Ludwig Institute for Cancer Research, Post Office Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia²

Received 14 December 2007/ Accepted 29 January 2008

Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3^–/– embryos, the Vegfc^–/–; Vegfd^–/– embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3^–/– embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3^neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc^+/– mice in the K14-VEGF-D; Vegfc^+/– compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.

Published ahead of print on 2 June 2008.

Present address: Lymphatic Development Laboratory, Cancer Research United Kingdom, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

Present address: Molecular/Cancer Biology Program, Institute of Biomedicine, University of Helsinki, Department of Molecular Medicine National Public Health Institute (KTL), Biomedicum Helsinki, P. O. B. 63 (Haartmaninkatu 8), University of Helsinki, 00014 Helsinki, Finland.

Present address: Vegenics Ltd., Level 1, 10 Wallace Avenue, Toorak, Victoria 3142, Australia.

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