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Angiogenesis induced by endothelial nitric oxide synthase gene through vascular endothelial growth factor expression in a rat hindlimb ischemia model.
Circulation. 2003 Nov 04; 108(18):2250-7.Circ

Abstract

BACKGROUND

Because the mechanism of the angiogenic property of nitric oxide (NO) was not fully understood in vivo, we focused on the role of vascular endothelial growth factor (VEGF) in angiogenesis induced by endothelial NO synthase (eNOS) gene transfer.

METHODS AND RESULTS

After intramuscular injection of eNOS DNA into a rat ischemic hindlimb, transfection of eNOS vector resulted in a significant increase in eNOS protein 1 week after transfection. In addition, tissue concentrations of nitrite and nitrate were significantly increased in rats transfected with the eNOS gene up to 2 weeks after transfection. The increase in tissue nitrite and nitrate concentrations was completely inhibited by NG-nitro-L-arginine methyl ester (L-NAME). In contrast, serum concentrations of nitrite and nitrate and blood pressure were not changed by eNOS gene transfer. Importantly, overexpression of the eNOS gene resulted in a significant increase in peripheral blood flow, whereas L-NAME inhibited the increase in blood flow. Interestingly, basal blood flow was significantly lower in rats treated with L-NAME than in control rats. A significant increase in capillary number was consistently detected in rats transfected with the eNOS gene at 4 weeks after transfection, accompanied by a significant increase in VEGF. Moreover, administration of neutralizing anti-VEGF antibody abolished the increase in blood flow and capillary density induced by eNOS plasmid injection.

CONCLUSIONS

Overall, intramuscular injection of bovine eNOS plasmid induced therapeutic angiogenesis in a rat ischemic hindlimb model, a potential therapy for peripheral arterial disease. The stimulation of angiogenesis by NO might be due to upregulation of local VEGF expression.

Authors+Show Affiliations

Division of Clinical Gene Therapy, Osaka University Medical School, 2-2 Yamada-oka, Suita 565-0871, Osaka, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14568906

Citation

Namba, Tsunetatsu, et al. "Angiogenesis Induced By Endothelial Nitric Oxide Synthase Gene Through Vascular Endothelial Growth Factor Expression in a Rat Hindlimb Ischemia Model." Circulation, vol. 108, no. 18, 2003, pp. 2250-7.
Namba T, Koike H, Murakami K, et al. Angiogenesis induced by endothelial nitric oxide synthase gene through vascular endothelial growth factor expression in a rat hindlimb ischemia model. Circulation. 2003;108(18):2250-7.
Namba, T., Koike, H., Murakami, K., Aoki, M., Makino, H., Hashiya, N., Ogihara, T., Kaneda, Y., Kohno, M., & Morishita, R. (2003). Angiogenesis induced by endothelial nitric oxide synthase gene through vascular endothelial growth factor expression in a rat hindlimb ischemia model. Circulation, 108(18), 2250-7.
Namba T, et al. Angiogenesis Induced By Endothelial Nitric Oxide Synthase Gene Through Vascular Endothelial Growth Factor Expression in a Rat Hindlimb Ischemia Model. Circulation. 2003 Nov 4;108(18):2250-7. PubMed PMID: 14568906.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiogenesis induced by endothelial nitric oxide synthase gene through vascular endothelial growth factor expression in a rat hindlimb ischemia model. AU - Namba,Tsunetatsu, AU - Koike,Hiromi, AU - Murakami,Kazushi, AU - Aoki,Motokuni, AU - Makino,Hirofumi, AU - Hashiya,Naotaka, AU - Ogihara,Toshio, AU - Kaneda,Yasufumi, AU - Kohno,Masakazu, AU - Morishita,Ryuichi, Y1 - 2003/10/20/ PY - 2003/10/22/pubmed PY - 2003/12/3/medline PY - 2003/10/22/entrez SP - 2250 EP - 7 JF - Circulation JO - Circulation VL - 108 IS - 18 N2 - BACKGROUND: Because the mechanism of the angiogenic property of nitric oxide (NO) was not fully understood in vivo, we focused on the role of vascular endothelial growth factor (VEGF) in angiogenesis induced by endothelial NO synthase (eNOS) gene transfer. METHODS AND RESULTS: After intramuscular injection of eNOS DNA into a rat ischemic hindlimb, transfection of eNOS vector resulted in a significant increase in eNOS protein 1 week after transfection. In addition, tissue concentrations of nitrite and nitrate were significantly increased in rats transfected with the eNOS gene up to 2 weeks after transfection. The increase in tissue nitrite and nitrate concentrations was completely inhibited by NG-nitro-L-arginine methyl ester (L-NAME). In contrast, serum concentrations of nitrite and nitrate and blood pressure were not changed by eNOS gene transfer. Importantly, overexpression of the eNOS gene resulted in a significant increase in peripheral blood flow, whereas L-NAME inhibited the increase in blood flow. Interestingly, basal blood flow was significantly lower in rats treated with L-NAME than in control rats. A significant increase in capillary number was consistently detected in rats transfected with the eNOS gene at 4 weeks after transfection, accompanied by a significant increase in VEGF. Moreover, administration of neutralizing anti-VEGF antibody abolished the increase in blood flow and capillary density induced by eNOS plasmid injection. CONCLUSIONS: Overall, intramuscular injection of bovine eNOS plasmid induced therapeutic angiogenesis in a rat ischemic hindlimb model, a potential therapy for peripheral arterial disease. The stimulation of angiogenesis by NO might be due to upregulation of local VEGF expression. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/14568906/Angiogenesis_induced_by_endothelial_nitric_oxide_synthase_gene_through_vascular_endothelial_growth_factor_expression_in_a_rat_hindlimb_ischemia_model_ L2 - https://www.ahajournals.org/doi/10.1161/01.CIR.0000093190.53478.78?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -