Glucocorticoid-regulated VEGF expression in ischemic skeletal muscle.
Vascular endothelial growth factor (VEGF) is a potent neovascular inducer. Gene therapeutic delivery of a plasmid DNA encoding VEGF has been shown to impart collateral vessel development in animal models of hindlimb ischemia. Constitutive, long-lived expression of VEGF through gene transfer, however, may result in hypervascularization and/or leaky blood vessels. To that end, the introduction of regulated VEGF gene transfer technology may provide a safer and more controlled therapy for ischemic tissues. We developed a glucocorticoid-regulated plasmid vector (pNGVL-hAP/GRE(5)-vegf-pA) for modulating VEGF gene expression. This plasmid possessed five tandem repeats of the glucocorticoid-responsive element and adenovirus major-late promoter driving the expression of the VEGF(165) cDNA. Intramuscular delivery of this plasmid to mice, and subsequent treatment with the synthetic glucocorticoid dexamethasone (DEX), led to greatly enhanced VEGF expression. Similar delivery to the gracillis muscle of New Zealand white rabbits that had undergone ligation of their femoral artery to induce ischemia exhibited increased VEGF expression and collateral vessel development only in the presence of DEX. Additionally, reintroduction of DEX at a time point during which initial VEGF transgene levels had subsided resulted in a vigorous reinduction of VEGF transgene expression. This new iteration of VEGF gene delivery provides for fine-tuned angiogenic factor-based therapy for tissues requiring neovascularization.
Halaby
Issam A
IA
Department of Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Lyden
Sean P
SP
Davies
Mark G
MG
Roztocil
Elisa
E
Salamone
Linda J
LJ
Brooks
Andrew I
AI
Green
Richard M
RM
Federoff
Howard J
HJ
Bowers
William J
WJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D005938:Glucocorticoids / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000893:Anti-Inflammatory Agents; D016228:Endothelial Growth Factors; D005938:Glucocorticoids; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003907:Dexamethasone