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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 1979-1987
Characterization of the vasculogenic block in the absence
of vascular endothelial growth factor-A
Victoria L. Bautch,
Sambra D. Redick,
Aaron Scalia,
Marco Harmaty,
Peter Carmeliet, and
Rebecca Rapoport
From the Department of Biology and the Program in Molecular Biology
and Genetics, University of North Carolina at Chapel Hill, Chapel Hill,
NC, and the Center for Transgene Technology and Gene
Therapy, KU Leuven, Leuven, Belgium.
Vascular endothelial growth factor (VEGF) signaling is required for
both differentiation and proliferation of vascular endothelium. Analysis of differentiated embryonic stem cells with one or both VEGF-A
alleles deleted showed that both the differentiation and the expansion
of endothelial cells are blocked during vasculogenesis. Blood island
formation was reduced by half in hemizygous mutant VEGF cultures and by
10-fold in homozygous mutant VEGF cultures. Homozygous mutant cultures
could be partially rescued by the addition of exogenous VEGF. RNA
levels for the endothelial adhesion receptors ICAM-2 and PECAM were
reduced in homozygous mutant cultures, but ICAM-2 RNA levels decreased
substantially, whereas PECAM RNA levels remained at hemizygous levels.
The quantitative data correlated with the antibody staining patterns
because cells that were not organized into vessels expressed
PECAM but not ICAM-2. These PECAM+ cell clumps accumulated
in mutant cultures as vessel density decreased, suggesting that they
were endothelial cell precursors blocked from maturation. A subset of
PECAM+ cells in clumps expressed stage-specific embryonic antigen-1
(SSEA-1), and all were ICAM-2( ) and CD34(), whereas vascular
endothelial cells incorporated into vessels were PECAM(+),
ICAM-2(+), CD34(+), and SSEA-1(). Analysis of flk-1 expression
indicated that a subset of vascular precursor cells coexpressed PECAM
and flk-1. These data suggest that VEGF signaling acts in a
dose-dependent manner to affect both a specific differentiation step
and the subsequent expansion of endothelial cells.
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