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

Abstract

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.

ACKNOWLEDGMENTS

This work was supported by grants from the National Health and Medical Research Council of Australia (NH&MRC) and the Cancer Council of Victoria, Australia (CCV). M.E.B. was supported by a postdoctoral fellowship from the CCV, S.A.S. was supported by a Pfizer Foundation senior research fellowship, and M.G.A. and M.L.H. were supported by senior research fellowships from the NH&MRC.

We thank Shin-Ichi Nishikawa for antibody against Vegfr-3, Patricia Lai, Dimitria Vranes, and Gillian Thornton for technical assistance, Peter Lock for DokR antiserum, and Tony Burgess for constructive comments.