Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy.
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.
Dor
Yuval
Y
Department of Molecular Biology, Hebrew University-Hadassah Medical School, MRI/MRS Laboratory, HBRC, Hadassah University Hospital, Jerusalem 91120, Israel.
Djonov
Valentin
V
Abramovitch
Rinat
R
Itin
Ahuva
A
Fishman
Glenn I
GI
Carmeliet
Peter
P
Goelman
Gadi
G
Keshet
Eli
E
D000818:Animals; D003331:Coronary Vessels; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D006321:Heart; D008099:Liver / Q000098:blood supply; D008222:Lymphokines / Q000235:genetics / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010477:Perfusion; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors