The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching

Nicholas C. Kappas, Gefei Zeng, John C. Chappell, Joseph B. Kearney, Surovi Hazarika, Kimberly G. Kallianos, Cam Patterson, Brian H. Annex, Victoria L. Bautch

Research output: Contribution to journalArticle

Abstract

Blood vessel formation requires the integrated regulation of endothelial cell proliferation and branching morphogenesis, but how this coordinated regulation is achieved is not well understood. Flt-1 (vascular endothelial growth factor [VEGF] receptor 1) is a high affinity VEGF-A receptor whose loss leads to vessel overgrowth and dysmorphogenesis. We examined the ability of Flt-1 isoform transgenes to rescue the vascular development of embryonic stem cell-derived flt-1- /- mutant vessels. Endothelial proliferation was equivalently rescued by both soluble (sFlt-1) and membrane-tethered (mFlt-1) isoforms, but only sFlt-1 rescued vessel branching. Flk-1 Tyr-1173 phosphorylation was increased in flt-1-/- mutant vessels and partially rescued by the Flt-1 isoform transgenes. sFlt-1-rescued vessels exhibited more heterogeneous levels of pFlk than did mFlt-1-rescued vessels, and reporter gene expression from the flt-1 locus was also heterogeneous in developing vessels. Our data support a model whereby sFlt-1 protein is more efficient than mFlt-1 at amplifying initial expression differences, and these amplified differences set up local discontinuities in VEGF-A ligand availability that are important for proper vessel branching.

Original languageEnglish (US)
Pages (from-to)847-858
Number of pages12
JournalJournal of Cell Biology
Volume181
Issue number5
DOIs
StatePublished - Jun 2 2008

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Vascular Endothelial Growth Factor Receptor-1
Blood Vessels
Protein Isoforms
Transgenes
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor
Embryonic Stem Cells
Morphogenesis
Reporter Genes
Endothelial Cells
Phosphorylation
Cell Proliferation
Ligands
Gene Expression
Membranes
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

Kappas, N. C., Zeng, G., Chappell, J. C., Kearney, J. B., Hazarika, S., Kallianos, K. G., ... Bautch, V. L. (2008). The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. Journal of Cell Biology, 181(5), 847-858. https://doi.org/10.1083/jcb.200709114

The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. / Kappas, Nicholas C.; Zeng, Gefei; Chappell, John C.; Kearney, Joseph B.; Hazarika, Surovi; Kallianos, Kimberly G.; Patterson, Cam; Annex, Brian H.; Bautch, Victoria L.

In: Journal of Cell Biology, Vol. 181, No. 5, 02.06.2008, p. 847-858.

Research output: Contribution to journalArticle

Kappas, NC, Zeng, G, Chappell, JC, Kearney, JB, Hazarika, S, Kallianos, KG, Patterson, C, Annex, BH & Bautch, VL 2008, 'The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching', Journal of Cell Biology, vol. 181, no. 5, pp. 847-858. https://doi.org/10.1083/jcb.200709114
Kappas NC, Zeng G, Chappell JC, Kearney JB, Hazarika S, Kallianos KG et al. The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. Journal of Cell Biology. 2008 Jun 2;181(5):847-858. https://doi.org/10.1083/jcb.200709114
Kappas, Nicholas C. ; Zeng, Gefei ; Chappell, John C. ; Kearney, Joseph B. ; Hazarika, Surovi ; Kallianos, Kimberly G. ; Patterson, Cam ; Annex, Brian H. ; Bautch, Victoria L. / The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. In: Journal of Cell Biology. 2008 ; Vol. 181, No. 5. pp. 847-858.
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