期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 634, 期 1-3, 页码 121-131出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2010.02.038
关键词
Sphingosine-1-phosphate; Poly(lactic-co-glycolic acid); Sustained release; Angiogenesis; Ischemia
资金
- JST (Japan Science and Technology Agency) Innovation Plaza Ishikawa
- Ministry of Education, Science, Sports and Culture of Japan
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [22590284, 21390057] Funding Source: KAKEN
Therapeutic angiogenesis is a promising strategy for treating ischemia. The lysophospholipid mediator sphingosine-l-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 Si P. and studied the effects of PLGA-S1P on neovascularization in murine ischemic hindlimbs. Intramuscular injections of PLGA-S1P stimulated blood flow in C578L/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, N omega-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. (C) 2010 Elsevier B.V. All rights reserved.
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