title: Angiogenesis induced by hVEGF165 gene controlled by hypoxic response elements in rabbit ischemia myocardium.
abstract: Hypoxic response element (HRE) offers satisfactory control over expression of hVEGF(165) in cell levels. However, the characteristics of regenerated blood vessels induced by long-term expression of transferred hVEGF(165) under control of HRE in vivo remain unknown. This study aims to investigate the effect of HRE on control of long-term expression of rAAV-delivered hVEGF(165) gene to ischemic myocardium and evaluate characteristics of angiogenesis induced by hVEGF(165) in vivo. Rabbit ischemic heart models were established surgically, rAAV-9HRE-hVEGF(165) was transfected to ischemia hearts subjected to 12 week ischemia. Molecular biological and immunohistochemistry were employed to determine expressions of HIF-1alpha and hVEGF(165). Microvessel densities of CD31(+) and alpha-SMA(+) regenerated vessels were also evaluated. Expressions of both hVEGF(165) mRNA and protein were upregulated following over-expression of endogenous HIF-1alpha early after ischemia, peaked at 4-6 weeks post-MI, declined, and approached pre-ischemia level at the end of 12 weeks of ischemia (P < 0.01). The significantly upregulated CD31 in hVEGF(165)-treated hearts presented from 8 to 12 weeks of ischemia compared with the control (P < 0.01). However, alpha-SMA expression was rapidly downregulated after ischemia and remained lower than the control level by the end of 12 weeks post-MI (P < 0.01). Overexpression of hVEGF(165) controlled by HIF-1alpha-HRE system shows a stably regional angiogenic efficacy in vivo. But, VEGF, as an early angiogenic cytokine, is inadequate for mediating histologically mature vessels in ischemia myocardium.
authors.affiliation: Center of Neurobiological Research, Hospital of Xuzhou Medical College; Xuzhou, Jiangsu 221002, People's Republic of China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Dong
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Xiahong
authors.initials: X
authors.lastname: Xu
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000229:Dependovirus; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D020218:Response Elements; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000199:Actins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A