Molecular and Cellular Biochemistry 264: 63–74, 2004. c  2004 Kluwer Academic Publishers. Printed in the Netherlands. Review Therapeutic myocardial angiogenesis with vascular endothelial growth factors Young-sup Yoon, Ingrid A. Johnson, Jong-Seon Park, Larry Diaz and Douglas W. Losordo Divisions of Cardiovascular Research and Cardiology, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA Abstract Emerging evidence has shown that administration of angiogenic growth factors, either as recombinant protein or by gene trans- fer, can augment tissue perfusion through neovascularization in animal models of myocardial and hindlimb ischemia. Many cytokines have angiogenic activity; one of those that have been best studied in animal models and clinical trials is vascular endothelial growth factor (VEGF). VEGF has been known to be a key regulator of physiologic and pathologic angiogenesis associated with tumor. Recently the effect of VEGF is not restricted to the direct angiogenic effect in vivo but includes mobiliza- tion of bone-marrow-derived endothelial progenitor cells and augmentation of postnatal vasculogenesis in situ. Clinical trials of therapeutic angiogenesis with VEGF in patients with end-stage coronary artery disease have shown increases in exercise time and reductions in anginal symptoms and have provided objective evidence of improved perfusion and left ventricular function. Larger scale placebo-controlled trials with recombinant protein (rhVEGF 165 ) have been limited to intracoronary and intravenous administration and have shown favorable trends in exercise time and angina frequency. Small-scale, placebo-controlled, ran- domized clinical trials of gene transfer (phVEGF-2) via thoracotomy or percutaneous intramyocardial delivery demonstrated significant improvement of both subjective symptoms and objective measures of myocardial ischemia. Both therapeutic modal- ities appear to be safe and well tolerated. Further studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors and the utility of adjunctive endothelial progenitor cell or other stem cell supplementation, to provide safe and effective therapeutic myocardial neovascularization. (Mol Cell Biochem 264: 63–74, 2004) Key words: gene therapy, vascular endothelial growth factor (VEGF), myocardium, neovascularization Introduction The therapeutic implications of angiogenic growth factors were identified by the pioneering work of Folkman three decades ago [1]. His laboratory’s work documented the extent to which tumor development was dependent upon neovascu- larization and suggested that this relationship might involve angiogenic growth factors that were specific for neoplasms. The gradual development of collateral circulation after severe coronary artery stenosis/occlusion has long been observed but the notion of using these phenomena for therapeutic purposes Address for offprints: Young-sup Yoon, Division of Cardiovascular Research, Caritas St. Elizabeth’s Medical Center, 736 Cambridge Street, Boston, MA 02135, USA (E-mail: young.yoon@tufts.edu) has only recently been applied. In fact, in many cases, the es- tablishment of ample collateral circulation has been known to be sufficient to preserve wall motion and prevent or reduce is- chemia at rest or during stress in clinical settings. Emulation or enhancement of this process by delivery of growth fac- tors to promote neovascularization may therefore be a useful therapeutic strategy for those with advanced vascular insuf- ficiency. This novel strategy, named “therapeutic angiogen- esis” [2], was tested both in animal models and in patients with critical limb ischemia [3, 4], and with advanced coronary artery disease unsuitable for revascularization; these patients