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Stabilized HIF‐1α is superior to VEGF for angiogenesis in skeletal muscle via adeno‐associated virus gene transfer
Author(s) -
Pajusola Katri,
Künnapuu Jaana,
Vuorikoski Sanna,
Soronen Jarkko,
André Helder,
Pereira Teresa,
Korpisalo Petra,
YläHerttuala Seppo,
Poellinger Lorenz,
Alitalo Kari
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-3720fje
Subject(s) - angiogenesis , vascular endothelial growth factor , adeno associated virus , neovascularization , vascular permeability , genetic enhancement , skeletal muscle , growth factor , chemistry , microbiology and biotechnology , cancer research , biology , recombinant dna , endocrinology , medicine , gene , vegf receptors , receptor , biochemistry , vector (molecular biology)
Therapeutic angiogenesis provides a potential alternative for the treatment of cardiovascular ischemic diseases. Vascular endothelial growth factor (VEGF) is an important component of the angiogenic response to ischemia. Here we used adeno‐associated virus (AAV) gene delivery to skeletal muscle to examine the effects of VEGF vs. a stabilized form of hypoxia‐inducible factor‐1α (HIF‐1α). The recombinant AAVs were injected into mouse tibialis anterior muscle, and their effects were analyzed by immunohistochemistry and functional assays. These analyses showed that stabilized HIF‐1 α markedly increase capillary sprouting and proliferation, whereas VEGF 164 or VEGF 120 induced only proliferation of endothelial cells without formation of proper capillary structures. The Evans Blue permeability assay indicated that, unlike VEGF, HIF‐1 α overexpression did not increase vascular leakiness in the transduced muscle. Doppler ultrasound imaging showed that vascular perfusion in the HIF‐1 α treated muscles was significantly enhanced when compared to the controls and not further improved by co‐expression of the arteriogenic growth factors angiopoietin‐1 or platelet‐derived growth factor‐B. Our results show that AAV‐mediated transduction of a stabilized form of HIF‐1 α can circumvent the problems associated with overexpression of individual angiogenic growth factors. HIF‐1 α should thus offer a potent alternative for pro‐angiogenic gene therapy.