Induction of vascular networks in adult organs: implications to proangiogenic therapy.

Abstract

Most therapeutic proangiogenic approaches rely on the premise that a single factor (e.g., VEGF) can induce new vascular loops properly connected to the existing vasculature of an ill-perfused organ (e.g., the ischemic myocardium). To gain insights into VEGF-driven neovascularization in the adult, in general, and to uncover inherent obstacles in VEGF-based therapeutic angiogenesis, we have used a transgenic system for conditional "on" and "off" switching of VEGF expression in selected adult organs and analytical methods for three-dimensional visualization of the induced vascular network. VEGF induces massive accumulation of endothelial progenitor cells and their subsequent coalescence into new vascular loops. Continual ramification of the vasculature and fusion of adjacent vessels culminate in formation of hemangioma-like vessels. In the absence of guiding cues, abnormal branching patterns and random connections with the existing network are formed. Following cessation of the VEGF stimulus, the acquired network undergoes extensive hemodynamic remodeling acting to "normalize" its architecture. Premature withdrawal of VEGF leads to regression of most acquired vessels, thus challenging the utility of therapeutic approaches relying on short stimulus duration. Overproduction of VEGF leads also to highly disruptive edema, thereby emphasizing the need to uncouple VEGF-induced permeability from its angiogenic activity. This genetic switch system thus highlights remaining problems critical for the implementation of proangiogenic therapy.