Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy

Yuval Dor, Valentin Djonov, Rinat Abramovitch, Ahuva Itin, Glenn I. Fishman, Peter Carmeliet, Gadi Goelman, Eli Keshets

Research output: Contribution to journalArticlepeer-review

342 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1939-1947
Number of pages9
JournalEMBO Journal
Volume21
Issue number8
DOIs
StatePublished - 15 Apr 2002
Externally publishedYes

Keywords

  • Angiogenesis
  • Conditional transgene
  • Therapy
  • VEGF

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