Improvement of vascular function by magnetic nanoparticle-assisted circumferential gene transfer into the native endothelium.
Gene therapy is a promising approach for chronic disorders that require continuous treatment such as cardiovascular disease. Overexpression of vasoprotective genes has generated encouraging results in animal models, but not in clinical trials. One major problem in humans is the delivery of sufficient amounts of genetic vectors to the endothelium which is impeded by blood flow, whereas prolonged stop-flow conditions impose the risk of ischemia. In the current study we have therefore developed a strategy for the efficient circumferential lentiviral gene transfer in the native endothelium under constant flow conditions. For that purpose we perfused vessels that were exposed to specially designed magnetic fields with complexes of lentivirus and magnetic nanoparticles thereby enabling overexpression of therapeutic genes such as endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF). This treatment enhanced NO and VEGF production in the transduced endothelium and resulted in a reduction of vascular tone and increased angiogenesis. Thus, the combination of MNPs with magnetic fields is an innovative strategy for site-specific and efficient vascular gene therapy.
Institute of Physiology I, Life & Brain Center, University Clinic of Bonn, Germany.
Sarah
S
Vosen
Institute of Physiology I, Life & Brain Center, University Clinic of Bonn, Germany.
Sarah
S
Rieck
Zentralinstitut für Medizintechnik (IMETUM), TU München, Germany.
Alexandra
A
Heidsieck
Institute of Experimental Oncology and Therapy Research, TU München, Germany.
Olga
O
Mykhaylyk
Institute of Pharmacology and Toxicology, University Clinic of Bonn, Germany.
Katrin
K
Zimmermann
Institute of Experimental Oncology and Therapy Research, TU München, Germany.
Christian
C
Plank
Zentralinstitut für Medizintechnik (IMETUM), TU München, Germany.
Bernhard
B
Gleich
Institute of Pharmacology and Toxicology, University Clinic of Bonn, Germany.
Alexander
A
Pfeifer
Institute of Physiology I, Life & Brain Center, University Clinic of Bonn, Germany.
Bernd K
BK
Fleischmann
Institute of Physiology I, Life & Brain Center, University Clinic of Bonn, Germany. Electronic address: dwenzel@uni-bonn.de.
Daniela
D
Wenzel
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009129:Muscle Tonus / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D058185:Magnetite Nanoparticles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
Endothelial function; Gene therapy; Magnetic nanoparticles; Vascular disease