on December 31, 2001
Circulation. 2001
Published online before print December 31, 2001, doi: 10.1161/hc0602.103673
Published online before print December 31, 2001, doi: 10.1161/hc0602.103673
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Submitted on October 12, 2001
From the Division of Cardiovascular Research
and Medicine (H.I., J.Y., C.K., S.M., H.M., S.H., M.S., T.L., J.M.I.,
T.A.), St Elizabeth's Medical Center, Tufts University School of
Medicine, Boston, Mass; and the Department of Physiology (H.I.) and
Institute of Medical Science (T.A.), Tokai University School of
Medicine, Japan. * To whom correspondence should be addressed. E-mail: asa777{at}aol.com.
Background—Previous
studies have established that bone marrow--derived
endothelial progenitor cells (EPCs) are present in
the systemic circulation. In the current study, we investigated the
hypothesis that gene transfer can be used to achieve phenotypic
modulation of EPCs. Methods and Results—In
vitro, ex vivo murine vascular endothelial growth
factor (VEGF) 164 gene transfer augmented EPC proliferative activity
and enhanced adhesion and incorporation of EPCs into quiescent as well
as activated endothelial cell monolayers. To
determine if such phenotypic modulation may facilitate therapeutic
neovascularization, heterologous EPCs transduced with adenovirus
encoding VEGF were administered to athymic nude mice with hindlimb
ischemia; neovascularization and blood flow recovery were both
improved, and limb necrosis/autoamputation were reduced by 63.7% in
comparison with control animals. The dose of EPCs used for the in vivo
experiments was 30 times less than that required in previous trials of
EPC transplantation to improve ischemic limb salvage. Necropsy
analysis of animals that received DiI-labeled VEGF-transduced
EPCs confirmed that enhanced EPC incorporation demonstrated in vitro
contributed to in vivo neovascularization as
well. Conclusions—In vitro,
VEGF EPC gene transfer enhances EPC proliferation, adhesion, and
incorporation into endothelial cell monolayers. In
vivo, gene-modified EPCs facilitate the strategy of cell
transplantation to augment naturally impaired neovascularization in an
animal model of experimentally induced limb
ischemia.
Revised on November 29, 2001
Accepted on December 14, 2001
Endothelial Progenitor Cell
Vascular Endothelial Growth Factor Gene Transfer for
Vascular Regeneration
Key words: gene therapy • endothelium • angiogenesis • ischemia
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