Copyright © 2005, European Society of Cardiology
Constitutively active HIF-1
improves perfusion and arterial remodeling in an endovascular model of limb ischemia
aThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
bVascular Program, Institute for Cell Engineering
cDepartments of Pediatrics, Medicine, Oncology, and Radiation Oncology
dThe McKusick–Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
* Corresponding author. Broadway Research Building, Suite 671, 733 North Broadway, Baltimore, MD 21205, United States. Fax: +1 443 287 5618. Email address: gsemenza{at}jhmi.edu
Objective: Hypoxia-inducible factor 1 (HIF-1) regulates the expression of angiogenic growth factors. We analyzed the effect of intramuscular (i.m.) delivery of AdCA5, an adenovirus encoding a constitutively active form of the HIF-1
subunit, in a novel model of limb ischemia.
Methods: AdCa5 or AdLacZ (6 x 108 pfu) was injected into male New Zealand White rabbits that were untreated or subjected to occlusion of the left superficial femoral artery by endovascular coils. Expression of mRNAs was quantified 1, 3, and 7 days after adenovirus injection into rabbits without occlusion. Calf blood pressure (BP), angiography, and immunohistochemical analyses were performed 14 days after arterial occlusion and adenovirus injection.
Results: AdCA5 increased the expression of HIF-1, monocyte chemotactic protein-1, placental growth factor, platelet-derived growth factor B, stromal-derived factor 1, and vascular endothelial growth factor (VEGF) mRNA as well as HIF-1 and VEGF protein. On day 14, AdCA5-injected limbs showed improved calf BP ratios (0.89 ± 0.13 vs. 0.51 ± 0.05, p = 0.02), angiographic perfusion scores (3.50 ± 0.56 vs. 8.33 ± 1.31, p = 0.007), and distal deep femoral artery diameter ratio (1.84 ± 0.25 vs. 0.93 ± 0.22, p = 0.02) relative to those receiving AdLacZ. The capillary/myocyte ratio (0.93 ± 0.03 vs. 0.78 ± 0.06, p = 0.04) and arterial luminal area (0.32 ± 0.05 mm2 vs. 0.21 ± 0.03 mm2, p = 0.04) were significantly increased in the AdCA5 group.
Conclusion: In a model that resembles atherosclerotic obstruction of peripheral arteries in patients, the i.m. administration of AdCA5 promoted arteriogenic and angiogenic responses.
KEYWORDS Angiogenesis; Collateral circulation; Gene therapy; Hypoxia-inducible factor
1 T.H.P. and H.K. contributed equally to this study.
Time for primary review 36 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Yamamoto, T. Matsuura, G. Narazaki, M. Sugitani, K. Tanaka, A. Maeda, G. Shiota, K. Sato, A. Yoshida, and I. Hisatome Synergistic effects of autologous cell and hepatocyte growth factor gene therapy for neovascularization in a murine model of hindlimb ischemia Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1329 - H1336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Alfranca VEGF therapy: a timely retreat Cardiovasc Res, September 1, 2009; 83(4): 611 - 612. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kimura, M. Iwano, D. F. Higgins, Y. Yamaguchi, K. Nakatani, K. Harada, A. Kubo, Y. Akai, E. B. Rankin, E. G. Neilson, et al. Stable expression of HIF-1{alpha} in tubular epithelial cells promotes interstitial fibrosis Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1023 - F1029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Cai, H. Zhong, M. Bosch-Marce, K. Fox-Talbot, L. Wang, C. Wei, M. A. Trush, and G. L. Semenza Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1{alpha} Cardiovasc Res, February 1, 2008; 77(3): 463 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bosch-Marce, H. Okuyama, J. B. Wesley, K. Sarkar, H. Kimura, Y. V. Liu, H. Zhang, M. Strazza, S. Rey, L. Savino, et al. Effects of Aging and Hypoxia-Inducible Factor-1 Activity on Angiogenic Cell Mobilization and Recovery of Perfusion After Limb Ischemia Circ. Res., December 7, 2007; 101(12): 1310 - 1318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Semenza Regulation of tissue perfusion in mammals by hypoxia-inducible factor 1 Exp Physiol, November 1, 2007; 92(6): 988 - 991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Baek, Y. V. Liu, K. R. McDonald, J. B. Wesley, M. E. Hubbi, H. Byun, and G. L. Semenza Spermidine/Spermine-N1-Acetyltransferase 2 Is an Essential Component of the Ubiquitin Ligase Complex That Regulates Hypoxia-inducible Factor 1{alpha} J. Biol. Chem., August 10, 2007; 282(32): 23572 - 23580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, L. Weigand, W. Lu, J.T. Sylvester, G. L. Semenza, and L. A. Shimoda Hypoxia Inducible Factor 1 Mediates Hypoxia-Induced TRPC Expression and Elevated Intracellular Ca2+ in Pulmonary Arterial Smooth Muscle Cells Circ. Res., June 23, 2006; 98(12): 1528 - 1537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Okuyama, B. Krishnamachary, Y. F. Zhou, H. Nagasawa, M. Bosch-Marce, and G. L. Semenza Expression of Vascular Endothelial Growth Factor Receptor 1 in Bone Marrow-derived Mesenchymal Cells Is Dependent on Hypoxia-inducible Factor 1 J. Biol. Chem., June 2, 2006; 281(22): 15554 - 15563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Luo, C. Jiang, A. J. Belanger, G. Y. Akita, S. C. Wadsworth, R. J. Gregory, and K. A. Vincent A Constitutively Active Hypoxia-Inducible Factor-1{alpha}/VP16 Hybrid Factor Activates Expression of the Human B-Type Natriuretic Peptide Gene Mol. Pharmacol., June 1, 2006; 69(6): 1953 - 1962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wilhide and W. K. Jones Potential Therapeutic Gene for the Treatment of Ischemic Disease: Ad2/Hypoxia-Inducible Factor-1{alpha} (HIF-1)/VP16 Enhances B-Type Natriuretic Peptide Gene Expression via a HIF-1-Responsive Element Mol. Pharmacol., June 1, 2006; 69(6): 1773 - 1778. [Abstract] [Full Text] [PDF]
|
|