Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 14, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp152
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Inducible AAV vectors induce functional angiogenesis in adult organisms via regulated VEGF expression
1 Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
2 Centre of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autonoma de Barcelona, Spain
3 Struttura Complessa di Medicina Nucleare, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Trieste, Italy
Address for correspondence: Mauro Giacca, MD PhD, Director, ICGEB Trieste, Head, Molecular Medicine Laboratory, Padriciano, 99, 34012 Trieste ( Italy), tel.: +39 040 375 7324, fax: +39 040 375 7380, e-mail: giacca{at}icgeb.org.
Aims: Members of the vascular endothelial growth factor (VEGF) family are among the most promising cytokines to induce neovascularization of ischemic tissues; however, their unregulated expression often results in major undesired effects. Here we describe the properties of inducible vectors based on the adeno-associated virus (AAV), allowing precise control of VEGF expression, and exploit these vectors to define the kinetics of the angiogenic response elicited by the factor.
Methods: Based on a tetracycline-inducible transactivator, we designed an AAV vector system allowing the pharmacological regulation of VEGF production in vivo, and tested its efficacy in inducing functional neoangiogenesis in both normoperfused and ischemic skeletal muscle in mice by a combination of histological, immunofluorescent and molecular imaging techniques.
Results: We observed that a prolonged expression of VEGF was required to determine the formation of stable vessels, able to persist upon withdrawal of the angiogenic stimulus. However, the vessels formed in the presence of continuous VEGF expression consisted mainly of dilated and leaky capillaries. As determined after pinhole scintigraphy, this abnormal vasculature accounted for a significant drop in functional tissue perfusion. In contrast, transient VEGF expression, followed by a period of VEGF withdrawal, allowed maintenance of functional perfusion under resting conditions and during exercise. This VEGF inducible system was highly effective in improving vascularization and function in a hindlimb ischemia model.
Conclusions: Together, these results clearly indicate that the fine tuning of VEGF expression is required to achieve the formation of a stable vasculature able to sustain functional neovascularization.
KEYWORDS AAV vectors; Angiogenesis; Gene Therapy; VEGF; Vessel maturation
Time for primary review: 23 Days
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Cardiovasc Res 2009 83: 611-612.
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