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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-01-0003.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2261-2267
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A chemically defined culture of VEGFR2+ cells derived
from embryonic stem cells reveals the role of VEGFR1 in tuning the
threshold for VEGF in developing endothelial cells
Masanori Hirashima,
Minetaro Ogawa,
Satomi Nishikawa,
Kazuyoshi Matsumura,
Kotomi Kawasaki,
Masabumi Shibuya, and
Shin-Ichi Nishikawa
From the Department of Molecular Genetics, Graduate
School of Medicine, Kyoto University, Japan; Department of Genetics,
Institute of Medical Science, University of Tokyo, Japan;
and Riken Center for Developmental Biology, Kobe, Japan.
Vascular endothelial growth factor (VEGF) is a major growth factor
for developing endothelial cells (ECs). Embryonic lethality due to
haploinsufficiency of VEGF in the mouse highlighted the strict dose
dependency of VEGF on embryonic vascular development. Here we
investigated the dose-dependent effects of VEGF on the differentiation
of ES cell-derived fetal liver kinase 1 (Flk-1)/VEGF receptor
2+ (VEGFR2+) mesodermal cells into ECs
on type IV collagen under a chemically defined serum-free condition.
These cells could grow even in the absence of VEGF, but differentiated
mostly into mural cells positive for  -smooth muscle actin. VEGF
supported in a dose-dependent manner the differentiation into ECs
defined by the expression of VE-cadherin, platelet-endothelial
cell adhesion molecule 1 (PECAM-1)/ CD31, CD34, and TIE2/TEK.
VEGF requirement was greater at late than at early phase of culture
during EC development, whereas response of VEGFR2+ cells to
VEGF-E, which is a virus-derived ligand for VEGFR2 but not for
Flt-1/VEGFR1, was not dose sensitive even at late phase of culture.
Delayed expression of VEGFR1 correlated with increased dose dependency
of VEGF. These results suggested that greater requirement of VEGF in
the maintenance than induction of ECs was due to the activity of VEGFR1
sequestering VEGF from VEGFR2 signal. The chemically defined serum-free
culture system described here provides a new tool for assessing
different factors for the proliferation and differentiation of
VEGFR2+ mesodermal cells.
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