title: Adenoviral-mediated delivery of early growth response factor-1 gene increases tissue perfusion in a murine model of hindlimb ischemia.
abstract: To test the hypothesis that overexpression of early growth response factor-1 (Egr-1) contributes to the revascularization of ischemic limbs, a constitutively active form of Egr-1 (Egr-1*) was made and evaluated in vitro and in vivo. Analyses of the transduced myocytes revealed significant upregulation of bFGF, PDGF-A, PDGF-B, IGF-II, and TGF-beta1. A coculture assay of the paracrine effects indicated that Ad-Egr-1* promoted proliferation and migration of endothelial cells. When Ad-Egr-1* was injected into the tibialis anterior muscle of mice, followed by explant culture in growth factor-reduced Matrigel, many capillary-like structures were observed in the Egr-1* group compared with minimal sprouting from the LacZ group, suggesting an angiogenic potential of Egr-1*. Next we evaluated Ad-Egr-1* in a murine model of hindlimb ischemia. Compared with slow revascularization in the control PBS or LacZ group, a rapid increase in tissue perfusion was observed in the Egr-1* group and the difference in flux ratio was statistically significant at day 7. In the injected muscle, expression of Egr-1*, upregulation of its target genes, and increased number of vessels staining positive for smooth muscle alpha-actin were observed. These results suggest that Egr-1 plays an important role in vascular recovery after occlusion and could be a potential target for therapeutic angiogenesis.
authors.affiliation: Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea.
authors.forename: Young-Sam
authors.initials: YS
authors.lastname: Lee
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Jang
authors.forename: Jeong-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Lee
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Koung
authors.initials: K
authors.lastname: Li Kim
authors.forename: In-Soon
authors.initials: IS
authors.lastname: Shin
authors.forename: Wonhee
authors.initials: W
authors.lastname: Suh
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Jeon
authors.forename: Jonghoe
authors.initials: J
authors.lastname: Byun
authors.forename: Duk-Kyung
authors.initials: DK
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006614:Hindlimb / Q000098:blood supply*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000098:blood supply; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger