| Angiopoietin-related growth factor enhances blood flow via activation of the ERK1/2-eNOS-NO pathway in a mouse hind-limb ischemia model. | |
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MedLine Citation:
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PMID: 18258819 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Transgenic mice overexpressing angiopoietin-related growth factor (AGF) exhibit enhanced angiogenesis, suggesting that AGF may be a useful drug target in ischemic disease. Our goal was to determine whether AGF enhances blood flow in a mouse hind-limb ischemia model and to define molecular mechanisms underlying AGF signaling in endothelial cells. METHODS AND RESULTS: Intramuscular injection of adenovirus harboring AGF into the ischemic limb increased AGF production, which increased blood flow through induction of angiogenesis and arteriogenesis, thereby reducing the necessity for limb amputation. In vitro analysis showed that exposing human umbilical venous endothelial cells to AGF increased nitric oxide (NO) production through activation of an ERK1/2-endothelial NO synthetase (eNOS) signaling pathway. AGF-stimulated eNOS phosphorylation, NO production, and endothelial cell migration were all abolished by specific MEK1/2 inhibitors. Moreover, AGF did not restore blood flow to ischemic hind-limbs of either mice receiving NOS inhibitor L-NAME or eNOS knockout mice. CONCLUSIONS: Activation of an ERK1/2-eNOS-NO pathway is a crucial signaling mechanism by which AGF increases blood flow through induction of angiogenesis and arteriogenesis. Further investigation of the regulation underlying AGF signaling pathway may contribute to develop a new clinical strategy for ischemic vascular diseases. |
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Authors:
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Takashi Urano; Yasuhiro Ito; Masaki Akao; Tomohiro Sawa; Keishi Miyata; Mitsuhisa Tabata; Tohru Morisada; Tai Hato; Masato Yano; Tsuyoshi Kadomatsu; Kunio Yasunaga; Rei Shibata; Toyoaki Murohara; Takaaki Akaike; Hidenobu Tanihara; Toshio Suda; Yuichi Oike |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-02-07 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 28 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-04-18 Completed Date: 2008-05-06 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 827-34 Citation Subset: IM |
Affiliation:
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Laboratory of Vascular Biology and Metabolism, Center for Integrated Medical Research, Department of Cell Differentiation, School of Medicine, Keio University, Tokyo, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiopoietins Animals Biological Factors / genetics, metabolism*, pharmacology Cell Movement / drug effects Cells, Cultured Disease Models, Animal Enzyme Activation Hindlimb / blood supply*, drug effects, metabolism Humans Ischemia / metabolism*, pathology Mice Mice, Inbred BALB C Mice, Knockout Mitogen-Activated Protein Kinase 1 / metabolism* Mitogen-Activated Protein Kinase 3 / metabolism* Muscle, Skeletal / blood supply, drug effects, metabolism Neovascularization, Physiologic / drug effects, physiology Nitric Oxide / metabolism* Nitric Oxide Synthase Type III / metabolism* RNA, Messenger / metabolism Regional Blood Flow / drug effects, physiology Umbilical Veins / drug effects, metabolism, pathology |
| Chemical | |
Reg. No./Substance:
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0/Angiopoietins; 0/Angptl6 protein, mouse; 0/Biological Factors; 0/RNA, Messenger; 10102-43-9/Nitric Oxide; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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