Published online before print June 21, 2007, doi: 10.1161/CIRCRESAHA.107.148676
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 21, 2006
Revised on May 21, 2007
Accepted on June 7, 2007
Therapeutic Arteriogenesis by Ultrasound-Mediated Vegf165 Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle
Howard Leong-Poi *;
From the Division of Cardiology (H.L.P., M.A.K., M.L., M.S., K.T.K., D.J.S.), Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Canada; the Cardiovascular Division (J.R.L.), Oregon Health and Sciences University, Portland; and the University of Virginia (A.L.K.), Charlottesville.
* To whom correspondence should be addressed. E-mail: leong-poih{at}smh.toronto.on.ca.
Current methods of gene delivery for therapeutic angiogenesis are invasive, requiring either intraarterial or intramuscular administration. A noninvasive method of gene delivery has been developed using ultrasound-mediated destruction of intravenously administered DNA-bearing carrier microbubbles during their microcirculatory transit. Here we show that chronic ischemia could be markedly improved by ultrasound-mediated destruction of microbubbles bearing vascular endothelial growth factor-165 (VEGF165) plasmid DNA. Using a model of severe chronic hindlimb ischemia in rats, we demonstrated that ultrasound mediated VEGF165/green fluorescent protein (GFP) plasmid delivery resulted in a significant improvement in microvascular blood flow by contrast-enhanced ultrasound, and an increased vessel density by fluorescent microangiography, with minimal changes in control groups. The improvement in tissue perfusion was attributed predominantly to increases in noncapillary blood volume or arteriogenesis, with perfusion peaking at 14 days after delivery, followed by a partial regression of neovascularization at 6 weeks. Transfection was localized predominantly to the vascular endothelium of arterioles in treated ischemic muscle. RT-PCR confirmed the presence of VEGF165/GFP mRNA within treated ischemic muscle, being highest at day 3 postdelivery, and subsequently decreasing, becoming almost undetectable by 6 weeks. We found a modulation of endogenous growth factor expression in VEGF-treated ischemic muscle, consistent with a biologic effect of ultrasound mediated gene delivery. The results of our study demonstrate the utility of ultrasonic destruction of plasmid-bearing microbubbles to induce therapeutic arteriogenesis in the setting of severe chronic ischemia.
Key words: angiogenesis • gene therapy • contrast ultrasound • peripheral vascular disease • chronic ischemia
Related Article:
- New Targeted Angiogenic Strategy: Bursting Bubbles
- Tomosaburo Takahashi and Hiroaki Matsubara
Circ. Res. 2007 101: 232-233.[Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  J. C. Chappell, J. Song, A. L. Klibanov, and R. J. Price Ultrasonic Microbubble Destruction Stimulates Therapeutic Arteriogenesis Via the CD18-Dependent Recruitment of Bone Marrow-Derived Cells Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1117 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. T. Rissanen, P. Korpisalo, H. Karvinen, T. Liimatainen, S. Laidinen, O. H. Grohn, and S. Yla-Herttuala High-Resolution Ultrasound Perfusion Imaging of Therapeutic Angiogenesis J. Am. Coll. Cardiol. Img., January 1, 2008; 1(1): 83 - 91. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Takahashi and H. Matsubara New Targeted Angiogenic Strategy: Bursting Bubbles Circ. Res., August 3, 2007; 101(3): 232 - 233. [Full Text] [PDF]
|
|