Transplantation of BM from wildtype donors into PlGF knockout recipients rescues the angiogenic defects, while PlGF promotes the mobilization of marrowderived hematopoietic and endothelial progenitors. Infusion of PlGF protein or adenoviral PlGF gene transfer enlarges collateral branches and angiogenesis in skin and ischemic limbs in preclinical animal models. Systemic delivery of recombinant PlGF also stimulates neovascularization in the infarct scar in mice when given during a one week period after MI.3 A recent study revealed that intramyocardial administration of PlGF1 protein increases endothelial cell density in the rat infarcted myocardium, inhibits left ventricular dilatation and preserves LV global function. However, the effect of PlGF on LV infarct size and cardiac regeneration via the recruitment of BM progenitors has not been studied previously. In addition, the therapeutic consequences of PlGF delivery on long-term cardiac performance after the arrest of PlGF administration remain unknown. This is relevant, as various angiogenic factors induce only a transient angiogenic response as long as they are being administered, and the newly formed vessels often regress once angiogenic therapy is arrested. Since injection of naked DNA is generally Wortmannin considered to be safer than viral gene transfer, we assessed the therapeutic potential of local intramyocardial delivery of a PlGF expression DNA vector. Our findings indicate that PlGF improved cardiac performance after acute MI by inducing not only local angiogenesis, but also vasculogenesis and cardiomyogenesis via recruitment of BMderived progenitors to the infarcted myocardium. The present data offer novel therapeutic opportunities for PlGF gene therapy in patients with ischemic heart disease. In this paper, we show that myocardial PlGF gene transfer is a promising novel therapeutic strategy to revascularize and regenerate the infarcted myocardium and improve its performance after MI. Besides enhancing angiogenesis, PlGF induced this beneficial effect via two novel mechanisms, i.e. stimulation of cardiomyocyte survival, and induction of cardiac myoangiogenesis by BM progenitor cells, recruited to the infarct. To the best of our knowledge, this is the first report to document such a therapeutic potential and these novel mechanisms of PlGF gene therapy for ischemic heart disease. Despite its discovery some 15 years ago now, the precise biological role of PlGF has remained puzzling for more than a decade. Over the last few years, however, PlGF has been increasingly recognized as contributing to the angiogenic NSC 136476 switch in numerous disorders. In addition, transgenic overexpression or viral gene delivery of PlGF, or administration of recombinant PlGF enhance angiogenesis and vessel maturation in the skin and ischemic limb, thus indicating that PlGF has sufficient angiogenic potency.