© 1997 American Heart Association, Inc.
Articles |
Adenovirus-Mediated Expression of the Secreted Form of Basic Fibroblast Growth Factor (FGF-2) Induces Cellular Proliferation and Angiogenesis In Vivo
From the Molecular Cardiology Unit, Department of Cardiology, Kyushu University School of Medicine, Japan.
Correspondence to Hikaru Ueno, MD, PhD, Department of Cardiology, Kyushu University School of Medicine, Fukuoka 812-82 Japan. E-mail ueno{at}cardiol.med.kyushu-u.ac.jp
Abstract Blood supply through collateral arteries is of
critical importance in occlusive arterial diseases such as
coronary atherosclerosis. Induction of
angiogenic growth factor within either the narrowing arteries or
jeopardized myocardium may promote angiogenesis in vivo,
leading to salvage of ischemic myocardium. We
constructed a replication-defective adenovirus (AdCAsFGF-2) coding for
human basic fibroblast growth factor (FGF)-2 that is modified, so that
its secretion will be facilitated, by tagging a signal sequence derived
from FGF-4. A large quantity of FGF-2 was detected in both the cell
lysate and culture medium of COS cells infected with AdCAsFGF-2,
indicating that FGF-2 was secreted at least partly from the infected
cells. The conditioned medium from the infected COS cells stimulated
DNA synthesis in and induced cellular proliferation of
arterial smooth muscle cells. These effects were eliminated
by adenovirus-mediated overexpression of a dominant-negative truncated
FGF-receptor type 1. Implantation of a gel of basement membrane
proteins containing fibroblasts infected with AdCAsFGF-2 into the
ventral subcutaneous space of mice induced extensive cellular
proliferation and the formation of functional arterioles. Cells
surrounding the vessels were positively immunostained with
antibodies recognizing either smooth muscle–specific 
-actin or
factor VIII antigen as a marker for
endothelium. These results suggest that
AdCAsFGF-2 may be useful for delivering functional FGF-2 into
tissues and may lead to therapeutic angiogenesis in vivo.
Key Words: adenovirus • gene therapy • angiogenesis • fibroblast growth factor • ischemic myocardium
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