Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb.
Critical limb ischemia is an important clinical problem that often leads to disability and limb loss. Vascular endothelial growth factor (VEGF), delivered either as recombinant protein or as gene therapy, has been shown to promote both collateral artery formation (arteriogenesis) and capillary angiogenesis in animal models of hindlimb ischemia. However, none of the previous studies has demonstrated an improvement in tissue hypoxia, the condition that drives the molecular response to ischemia. Furthermore, the optimal vector and route of gene delivery have not been determined. Recently, adeno-associated viral (AAV) vectors, which efficiently transduce skeletal muscle and produce sustained transgene expression, have been used as gene therapy vectors. We asked whether an intra-arterial injection of AAV-VEGF(165) normalizes muscle oxygen tension by increasing skeletal muscle oxygen tension, and promotes arteriogenesis and angiogenesis in a rat model of severe hindlimb ischemia. We found that AAV-VEGF treatment normalized muscle oxygen tension in the ischemic limb. In contrast, vehicle and AAV-lacZ-treated limbs remained ischemic. Collateral arteries were more numerous in AAV-VEGF-treated rats, but, surprisingly, capillaries were not. We conclude that intra-arterial AAV-mediated gene transfer of AAV-VEGF(165) normalizes muscle oxygen tension and leads to arteriogenesis in rats with severe hindlimb ischemia.
Chang
David S
DS
Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
Su
Hua
H
Tang
Gale L
GL
Brevetti
Lucy S
LS
Sarkar
Rajabrata
R
Wang
Rong
R
Kan
Yuet W
YW
Messina
Louis M
LM
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D000229:Dependovirus / Q000235:genetics*; D016228:Endothelial Growth Factors / Q000097:blood / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006614:Hindlimb / Q000098:blood supply*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D007511:Ischemia / Q000503:physiopathology*; D008222:Lymphokines / Q000097:blood / Q000235:genetics*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001616:beta-Galactosidase / Q000235:genetics
D017931:DNA Primers; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001616:beta-Galactosidase; D010100:Oxygen