| Sustained delivery of sphingosine-1-phosphate using poly(lactic-co-glycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice. | |
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MedLine Citation:
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PMID: 20206620 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Therapeutic angiogenesis is a promising strategy for treating ischemia. The lysophospholipid mediator sphingosine-1-phosphate (S1P) acts on vascular endothelial cells to stimulate migration and tube formation, and plays the critical role in developmental angiogenesis. We developed poly(lactic-co-glycolic-acid) (PLGA)-based S1P-containing microparticles (PLGA-S1P), which are biodegradable and continuously release S1P, and studied the effects of PLGA-S1P on neovascularization in murine ischemic hindlimbs. Intramuscular injections of PLGA-S1P stimulated blood flow in C57BL/6 mice dose-dependently, with repeated administrations at a 3-day interval, rather than a single bolus or 6-day interval, over 28 days conferring the optimal stimulating effect. In Balb/c mice that exhibit limb necrosis and dysfunction due to retarded blood flow recovery, injections of PLGA-S1P stimulated blood flow with alleviation of limb necrosis and dysfunction. PLGA-S1P alone did not induce edema in ischemic limbs, and rather blocked vascular endothelial growth factor-induced edema. PLGA-S1P not only increased the microvessel densities in ischemic muscle, but promoted coverage of vessels with smooth muscle cells and pericytes, thus stabilizing vessels. PLGA-S1P stimulated Akt and ERK with increased phosphorylation of endothelial nitric oxide synthase in ischemic muscle. The effects of the nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methylester, showed that PLGA-S1P-induced blood flow stimulation was partially dependent on nitric oxide. Injections of PLGA-S1P also increased the expression of angiogenic factors and the recruitment of CD45-, CD11b- and Gr-1-positive myeloid cells, which are implicated in post-ischemic angiogenesis, into ischemic muscle. These results indicate that PLGA-based, sustained local delivery of S1P is a potentially useful therapeutic modality for stimulating post-ischemic angiogenesis. |
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Authors:
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Xun Qi; Yasuo Okamoto; Tomomi Murakawa; Fei Wang; Osamu Oyama; Ryunosuke Ohkawa; Kazuaki Yoshioka; Wa Du; Naotoshi Sugimoto; Yutaka Yatomi; Noriko Takuwa; Yoh Takuwa |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-03 |
Journal Detail:
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Title: European journal of pharmacology Volume: 634 ISSN: 1879-0712 ISO Abbreviation: Eur. J. Pharmacol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-12 Completed Date: 2010-11-01 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1254354 Medline TA: Eur J Pharmacol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 121-31 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier B.V. All rights reserved. |
Affiliation:
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Department of Physiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Delayed-Action Preparations / administration & dosage Disease Models, Animal Extracellular Signal-Regulated MAP Kinases / physiology* Hindlimb / blood supply, drug effects Ischemia / drug therapy*, enzymology, physiopathology* Lactic Acid / administration & dosage* Lysophospholipids / administration & dosage* Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Microspheres Neovascularization, Pathologic / drug therapy, enzymology, physiopathology Neovascularization, Physiologic / drug effects*, physiology Nitric Oxide Synthase Type III / physiology* Polyglycolic Acid / administration & dosage* Proto-Oncogene Proteins c-akt / physiology* Random Allocation Regional Blood Flow / drug effects, physiology Sphingosine / administration & dosage, analogs & derivatives* |
| Chemical | |
Reg. No./Substance:
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0/Delayed-Action Preparations; 0/Lysophospholipids; 0/polylactic acid-polyglycolic acid copolymer; 123-78-4/Sphingosine; 26009-03-0/Polyglycolic Acid; 26993-30-6/sphingosine 1-phosphate; 50-21-5/Lactic Acid; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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