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Molecular and Cellular Biology, January 2005, p. 346-354, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.346-354.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Membrane Fixation of Vascular Endothelial Growth Factor Receptor 1 Ligand-Binding Domain Is Important for Vasculogenesis and Angiogenesis in Mice

Sachie Hiratsuka,1,2 Kazuki Nakao,3 Kenji Nakamura,4 Motoya Katsuki,5 Yoshiro Maru,2 and Masabumi Shibuya1*

Division of Genetics, Institute of Medical Science, University of Tokyo,1 Department of Pharmacology, Tokyo Women's Medical University School of Medicine,2 Reproductive Engineering Section, Mouse Genome Technology Center, Mitsubishi Kagaku Institute of Life Science, Tokyo,4 Laboratory for Animal Resource and Genetic Engineering, RIKEN, Center for Developmental Biology, Hyogo,3 National Institute for Basic Biology, Aichi, Japan5

Received 24 June 2004/ Returned for modification 4 August 2004/ Accepted 3 October 2004

Vascular endothelial growth factor (VEGF) regulates vasculogenesis and angiogenesis by using two tyrosine kinase receptors, VEGFR1 and VEGFR2. VEGFR1 null mutant mice die on embryonic day 8.5 (E8.5) to E9.0 due to an overgrowth of endothelial cells and vascular disorganization, suggesting that VEGFR1 plays a negative role in angiogenesis. We previously showed that the tyrosine kinase (TK) domain of VEGFR1 is dispensable for embryogenesis, since VEGFR1 TK-deficient mice survived and were basically healthy. However, the molecular basis for this is not yet clearly understood. To test the hypothesis that the specific role of VEGFR1 during early embryogenesis is to recruit its ligand to the cell membrane, we deleted the transmembrane (TM) domain in TK-deficient VEGFR1 mice. Surprisingly, about half of the VEGFR1(TM-TK)-deficient mice succumbed to embryonic lethality due to a poor development of blood vessels, whereas other mice were healthy. In VEGFR1(TM-TK)–/– mice with growth arrest, membrane-targeted VEGF was reduced, resulting in the suppression of VEGFR2 phosphorylation. Furthermore, the embryonic lethality in VEGFR1(TM-TK)–/– mice was significantly increased to 80 to 90% when the genotype of VEGFR2 was changed from homozygous (+/+) to heterozygous (+/–) in 129/C57BL6 mice. These results strongly suggest that the membrane-fixed ligand-binding region of VEGFR1 traps VEGF for the appropriate regulation of VEGF signaling in vascular endothelial cells during early embryogenesis.

* Corresponding author. Mailing address: Division of Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. Phone: 81-3-5449-5550. Fax: 81-3-5449-5425. E-mail: shibuya{at}ims.u-tokyo.ac.jp.

Molecular and Cellular Biology, January 2005, p. 346-354, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.346-354.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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