The Specificity of Receptor Binding by Vascular Endothelial Growth Factor-D Is Different in Mouse and Man

Megan E. Baldwin, Bruno Catimel, Edouard C. Nice, Sally Roufail, Nathan E. Hall, Kaye L. Stenvers, Marika J. Karkkainen, Kari Alitalo, Steven A. Stacker, Marc G. Achen

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117 Citations (Scopus)

Abstract

Human vascular endothelial growth factor-D (VEGF-D) binds and activates VEGFR-2 and VEGFR-3, receptors expressed on vascular and lymphatic endothelial cells. As VEGFR-2 signals for angiogenesis and VEGFR-3 is thought to signal for lymphangiogenesis, it was proposed that VEGF-D stimulates growth of blood vessels and lymphatic vessels into regions of embryos and tumors. Here we report the unexpected finding that mouse VEGF-D fails to bind mouse VEGFR-2 but binds and cross-links VEGFR-3 as demonstrated by biosensor analysis with immobilized receptor domains and bioassays of VEGFR-2 and VEGFR-3 cross-linking. Mutation of amino acids in mouse VEGF-D to those in the human homologue indicated that residues important for the VEGFR-2 interaction are clustered at, or are near, the predicted receptor-binding surface. Coordinated expression of VEGF-D and VEGFR-3 in mouse embryos was detected in the developing skin where the VEGF-D gene was expressed in a layer of cells beneath the developing epidermis and VEGFR-3 was localized on a network of vessels immediately beneath the VEGF-D-positive cells. This suggests that VEGF-D and VEGFR-3 may play a role in establishing vessels of the skin by a paracrine mechanism. Our study of receptor specificity suggests that VEGF-D may have different biological functions in mouse and man.

Original languageEnglish
Pages (from-to)19166-19171
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number22
DOIs
Publication statusPublished - 1 Jun 2001
Externally publishedYes

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