Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration

• Published in: Circulation (New York, N.Y.) N.Y.), 2002-02, Vol.105 (6), p.732-738
• Main Authors: IWAGURO, Hideki, YAMAGUCHI, Jun-Ichi, KALKA, Christoph, MURASAWA, Satoshi, MASUDA, Haruchika, HAYASHI, Shin-Ichiro, SILVER, Marcy, TONG LI, ISNER, Jeffrey M, ASAHARA, Takayuki
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Biological and medical sciences; Cardiology. Vascular system; Cell Count; Cell Division - drug effects; Cell Division - physiology; Cells, Cultured; Coronary heart disease; Dendritic Cells; Disease Models, Animal; Endothelial Growth Factors - genetics; Endothelial Growth Factors - metabolism; Endothelial Growth Factors - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Female; Gene Transfer, Horizontal; Genetic Therapy - methods; Genetic Vectors - genetics; Genetic Vectors - metabolism; Genetic Vectors - pharmacology; Heart; Humans; Ischemia - drug therapy; Ischemia - pathology; Ischemia - physiopathology; Lymphokines - genetics; Lymphokines - metabolism; Lymphokines - pharmacology; Medical sciences; Mice; Mice, Nude; Microcirculation - drug effects; Microcirculation - metabolism; Microcirculation - pathology; Muscle, Skeletal - blood supply; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Neovascularization, Physiologic - drug effects; Regeneration - drug effects; Stem Cell Transplantation; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Transgenes; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/hc0602.103673

Previous studies have established that bone marrow-derived endothelial progenitor cells (EPCs) are present in the systemic circulation. In the current study, we investigated the hypothesis that gene transfer can be used to achieve phenotypic modulation of EPCs. In vitro, ex vivo murine vascular endothelial growth factor (VEGF) 164 gene transfer augmented EPC proliferative activity and enhanced adhesion and incorporation of EPCs into quiescent as well as activated endothelial cell monolayers. To determine if such phenotypic modulation may facilitate therapeutic neovascularization, heterologous EPCs transduced with adenovirus encoding VEGF were administered to athymic nude mice with hindlimb ischemia; neovascularization and blood flow recovery were both improved, and limb necrosis/autoamputation were reduced by 63.7% in comparison with control animals. The dose of EPCs used for the in vivo experiments was 30 times less than that required in previous trials of EPC transplantation to improve ischemic limb salvage. Necropsy analysis of animals that received DiI-labeled VEGF-transduced EPCs confirmed that enhanced EPC incorporation demonstrated in vitro contributed to in vivo neovascularization as well. In vitro, VEGF EPC gene transfer enhances EPC proliferation, adhesion, and incorporation into endothelial cell monolayers. In vivo, gene-modified EPCs facilitate the strategy of cell transplantation to augment naturally impaired neovascularization in an animal model of experimentally induced limb ischemia.