(Circulation. 2000;102:2255.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Angiogenesis Is Induced in a Rabbit Model of Hindlimb Ischemia by Naked DNA Encoding an HIF-1
/VP16 Hybrid Transcription Factor
From Genzyme Corp (K.A.V., Y.L., C.J., M.A.G., G.Y.A., R.J.G.) Framingham, Mass.; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School (M.A.G.); and Department of Medicine and Biomedical Research, St Elizabeth’s Medical Center, Tufts Medical School (K.-G.S., M.M., R.A.T., J.M.I.), Boston, Mass. The first 2 authors contributed equally to this work.
Correspondence to Jeffrey M. Isner, MD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.com
Background—Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that regulates expression of genes involved in O2 homeostasis, including vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis. We sought to exploit this native adaptive response to hypoxia as a treatment for chronic ischemia.
Methods and Results—A hybrid protein consisting of DNA-binding
and dimerization domains from the HIF-1
subunit and the
transactivation domain from herpes simplex virus VP16 protein was
constructed to create a strong, constitutive transcriptional
activator. After transfection into HeLa, C6, and Hep3B
cells, this chimeric transcription factor was shown to activate
expression of the endogenous VEGF gene, as well as several
other HIF-1 target genes in vitro. The bioactivity of HIF-1/VP16
hybrid gene transfer in vivo was examined in a rabbit model of hindlimb
ischemia. Administration of HIF-1/VP16 was associated with
significant improvements in calf blood pressure ratio, angiographic
score, resting and maximal regional blood flow, and capillary density
(all P<0.01).
Conclusions—The HIF-1/VP16 hybrid transcription factor
is able to promote significant improvement in perfusion of an
ischemic limb. These results confirm the feasibility of a novel
approach for therapeutic angiogenesis in which neovascularization may
be achieved indirectly by use of a transcriptional regulatory strategy.
Key Words: transcription factors • ischemia • angiogenesis • collateral circulation • growth substances
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|
|
|
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|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 W. G. Kaelin Jr. How oxygen makes its presence felt Genes & Dev., June 15, 2002; 16(12): 1441 - 1445. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
J. Li, N. W. Shworak, and M. Simons Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1{alpha}-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites J. Cell Sci., January 5, 2002; 115(9): 1951 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Brusselmans, F. Bono, P. Maxwell, Y. Dor, M. Dewerchin, D. Collen, J.-M. Herbert, and P. Carmeliet Hypoxia-inducible Factor-2alpha (HIF-2alpha ) Is Involved in the Apoptotic Response to Hypoglycemia but Not to Hypoxia J. Biol. Chem., October 12, 2001; 276(42): 39192 - 39196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Bruick and S. L. McKnight Building better vasculature Genes & Dev., October 1, 2001; 15(19): 2497 - 2502. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
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P. Oettgen Transcriptional Regulation of Vascular Development Circ. Res., August 31, 2001; 89(5): 380 - 388. [Abstract] [Full Text] [PDF]
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