Background-New revascularization therapies are urgently needed for patients with severe coronary heart disease who lack conventional treatment options. Methods and Results-We describe a new proangiogenic approach for these no-option patients using adenoviral (Ad) intramyocardial vascular endothelial growth factor (VEGF)-B 186 gene transfer, which induces myocardium-specific angiogenesis and arteriogenesis in pigs and rabbits. After acute infarction, AdVEGF-B 186 increased blood vessel area, perfusion, ejection fraction, and collateral artery formation and induced changes toward an ischemia-resistant myocardial phenotype. Soluble VEGF receptor-1 and soluble neuropilin receptor-1 reduced the effects of AdVEGF-B 186 , whereas neither soluble VEGF receptor-2 nor inhibition of nitric oxide production had this result. Key Words: angiogenesis Ⅲ gene therapy Ⅲ metabolism Ⅲ myocardial infarction S evere coronary heart disease is still a leading cause of death in developed countries in spite of improved management of risk factors and more effective treatments. It is estimated that approximately 5 million people in the United States and the European Union have ischemic heart disease; however, a steadily increasing number of patients fall into a category in which currently available revascularization techniques cannot be applied. This is especially true of elderly patients who have had multiple bypass and stenting operations. 1 It is estimated that these patients represent up to 3% to 5% of all patients in specialty cardiology clinics. Thus, there is a clear need to develop efficient, minimally invasive procedures for the treatment of these no-option patients. Clinical Perspective p 856Therapeutic vascular growth (ie, angiogenesis and arteriogenesis) with genes or proteins has been suggested as an alternative approach for the treatment of these patients. 2 Vascular endothelial growth factors (VEGFs) are potent inducers of vascular growth via binding to 3 tyrosine kinase receptors (VEGFRs). VEGFR-2 is the main regulator of angiogenesis, exerting its function via nitric oxide production, whereas the role of VEGFR-1 is far less defined. 3 VEGF-B 4 and placental growth factor (PlGF) 3 share structural and functional characteristics and bind to VEGFR-1, whereas VEGF-A 5 binds to both VEGFR-1 and VEGFR-2. 846 Circulation

Rationale: We studied a possibility that shRNAs can lead to transcriptional gene activation at the promoter level via epigenetic mechanism. Objective: The purpose of this study was to test the effects on vascular endothelial growth factor (VEGF-A) expression by promoter targeted small hairpin RNAs (shRNAs) in vitro and in experimental animals in vivo using stable local lentiviral gene transfer. Methods and Results