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
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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DOI：
10.1016/j.ejphar.2010.02.038
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发表时间：
2010-05-25
影响因子：
5
通讯作者：
Takuwa, Yoh
中科院分区：
文献类型：
--
作者：
Qi, Xun;Okamoto, Yasuo;Takuwa, Yoh
治疗性血管生成是治疗缺血的一种有前途的策略。溶血磷脂介体鞘氨醇-l-磷酸（S1 P）作用于血管内皮细胞以刺激迁移和管形成，并且在发育性血管生成中起关键作用。我们开发了基于聚乳酸-羟基乙酸共聚物（PLGA）的含S1 P的微粒（PLGA-S1 P），它是可生物降解的，并持续释放SiP。研究了PLGA-S1 P对小鼠缺血后肢新生血管的影响。肌内注射PLGA-S1 P以剂量依赖性方式刺激C578 L/6小鼠的血流，在28天内以3天的间隔重复给药，而不是单次推注或6天的间隔，从而获得最佳刺激效果。在由于血流恢复迟缓而表现出肢体坏死和功能障碍的Balb/c小鼠中，注射PLGA-S1 P刺激了血流，缓解了肢体坏死和功能障碍。单独的PLGA-S1 P不会诱导缺血肢体的水肿，而是阻断血管内皮生长因子诱导的水肿。PLGA-S1 P不仅增加了缺血肌肉中的微血管密度，而且促进了平滑肌细胞和周细胞对血管的覆盖，从而稳定了血管。PLGA-S1 P刺激Akt和ERK，增加缺血肌肉中内皮型一氧化氮合酶的磷酸化。一氧化氮合酶抑制剂N ω-硝基-L-精氨酸甲酯的作用表明，PLGA-S1 P诱导的血流刺激部分依赖于一氧化氮。注射PLGA-S1 P还增加了血管生成因子的表达和CD 45-、CD 11b-和Gr-1-阳性髓样细胞的募集，这些细胞参与缺血后血管生成，进入缺血肌肉。这些结果表明，基于PLGA的持续局部递送S1 P是刺激缺血后血管生成的潜在有用的治疗方式。(C)2010爱思唯尔有限公司版权所有。
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.