Therapeutic angiogenesis for cardiovascular disease

Abstract

The identification of angiogenic growth factors, such as vascular endothelial growth factor and fibroblast growth factor, has fueled interest in using such factors to induce therapeutic angiogenesis. The results of numerous animal studies and clinical trials have offered promise for new treatment strategies for various ischemic diseases. Increased understanding of the cellular and molecular biology of vessel growth has, however, prompted investigators and clinicians alike to reconsider the complexity of therapeutic angiogenesis. The realization that formation of a stable vessel is a complex, multistep process may provide useful insights into the design of the next generation of angiogenesis therapy.

Figure 1

Assembly of a stable vessel. Local increases in angiogenic factors such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) during new vessel formation destabilize a portion of an existing vessel (usually a venule). Destabilization is associated with increased angiopoietin (ang)-2 expression and with pericyte activation, matrix remodeling, and induction of pericyte and endothelial cell (EC) migration and proliferation. Newly formed vessels may be dependent on exogenous factors for their survival until they have been remodeled to mature structures. Remodeling involves EC recruitment of pericyte/smooth muscle cell (SMC) precursors via endothelial-derived platelet-derived growth factor (PDGF). Once the mural cell precursor makes contact with the vessel, transforming growth factor (TGF)-β is activated, which in turn suppresses the proliferation and migration and induces the differentiation into SMC/pericytes. In addition to TGF-β, ang-1 produced by the SMC/pericytes is also involved in the stabilization and maintenance of the stable mature vessel. aFGF, acidic fibroblast growth factor; bFGF, basic fibroblast growth factor; CEP, circulating endothelial precursor.