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Vascular Endothelial Growth Factor D Is Dispensable for Development of the Lymphatic System

Megan E. Baldwin,^1, Michael M. Halford,^1, Sally Roufail,¹ Richard A. Williams,² Margaret L. Hibbs,¹ Dianne Grail,¹ Hajime Kubo,³ Steven A. Stacker,¹ and Marc G. Achen^1*

Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria 3050,¹ Department of Pathology, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Parkville, Victoria 3052, Australia,² Molecular and Cancer Research Unit, HMRO, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto, Japan³

Received 24 August 2004/ Returned for modification 10 October 2004/ Accepted 7 December 2004

Vascular endothelial growth factor receptor 3 (Vegfr-3) is a tyrosine kinase that is expressed on the lymphatic endothelium and that signals for the growth of the lymphatic vessels (lymphangiogenesis). Vegf-d, a secreted glycoprotein, is one of two known activating ligands for Vegfr-3, the other being Vegf-c. Vegf-d stimulates lymphangiogenesis in tissues and tumors; however, its role in embryonic development was previously unknown. Here we report the generation and analysis of mutant mice deficient for Vegf-d. Vegf-d-deficient mice were healthy and fertile, had normal body mass, and displayed no pathologic changes consistent with a defect in lymphatic function. The lungs, sites of strong Vegf-d gene expression during embryogenesis in wild-type mice, were normal in Vegf-d-deficient mice with respect to tissue mass and morphology, except that the abundance of the lymphatics adjacent to bronchioles was slightly reduced. Dye uptake experiments indicated that large lymphatics under the skin were present in normal locations and were functional. Smaller dermal lymphatics were similar in number, location, and function to those in wild-type controls. The lack of a profound lymphatic phenotype in Vegf-d-deficient mice suggests that Vegf-d does not play a major role in lymphatic development or that Vegf-c or another, as-yet-unknown activating Vegfr-3 ligand can compensate for Vegf-d during development.

Present address: Genentech Inc., South San Francisco, CA 94080-4990.

Present address: Center for Developmental Biology and Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133.

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