The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel
Authors Kappas NC, Zeng G, Chappell JC, Kearney JB, Hazarika S, Kallianos KG, Patterson
C, Annex BH, Bautch VL
Submitted By Thomas Coffman on 8/11/2010
Status Published
Journal The Journal of cell biology
Year 2008
Date Published 6/2/2008
Volume : Pages 181 : 847 - 858
PubMed Reference 18504303
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.

Investigators with authorship
Thomas CoffmanDuke University Medical Center