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| Subject Categories: Differentiation & Death | Molecular Biology of Disease |
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| The EMBO Journal
(2002) 21, 1939–1947, doi: 10.1093/emboj/21.8.1939 |
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| Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy |
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| Yuval Dor1, Valentin Djonov2, Rinat Abramovitch3, Ahuva Itin1, Glenn I. Fishman4, Peter Carmeliet5, Gadi Goelman2 and Eli Keshet1 |
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1 Department of Molecular Biology, Hebrew University−Hadassah Medical School, Jerusalem 91120, Israel 2 Department of Anatomy, Berne University, Switzerland 3 MRI/MRS Laboratory, HBRC, Hadassah University Hospital, Jerusalem 91120, Israel 4 Section of Myocardial Biology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA 5 The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, B-3000, Leuven, Belgium To whom correspondence should be addressed Eli Keshet, keshet@cc.huji.ac.il Received 13 November 2001; Revised 15 February 2002; Accepted 20 February 2002. |
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| Abstract |
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| To gain insight into neovascularization of adult organs and to uncover inherent obstacles in vascular endothelial growth factor (VEGF)-based therapeutic angiogenesis, a transgenic system for conditional switching of VEGF expression was devised. The system allows for a reversible induction of VEGF specifically in the heart muscle or liver at any selected schedule, thereby circumventing embryonic lethality due to developmental misexpression of VEGF. Using this system, we demonstrate a progressive, unlimited ramification of the existing vasculature. In the absence of spatial cues, however, abnormal vascular trees were produced, a consequence of chaotic connections with the existing network and formation of irregularly shaped sac-like vessels. VEGF also caused a massive and highly disruptive edema. Importantly, premature cessation of the VEGF stimulus led to regression of most acquired vessels, thus challenging the utility of therapeutic approaches relying on short stimulus duration. A critical transition point was defined beyond which remodeled new vessels persisted for months after withdrawing VEGF, conferring a long-term improvement in organ perfusion. This novel genetic system thus highlights remaining problems in the implementation of pro-angiogenic therapy. |
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| Keywords: angiogenesis, conditional transgene, therapy, VEGF |
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