The lysophospholipid mediator sphingosine-1-phosphate promotes angiogenesis in vivo in ischaemic hindlimbs of mice
The lysophospholipid mediator sphingosine-1-phosphate promotes angiogenesis in vivo in ischaemic hindlimbs of mice
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DOI：
10.1093/cvr/cvn002
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发表时间：
2008-05-01
影响因子：
10.8
通讯作者：
Takuwa, Yoh
中科院分区：
文献类型：
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作者：
Oyama, Osamu;Sugimoto, Naotoshi;Takuwa, Yoh
目的：溶血磷脂介体鞘氨醇-1-磷酸（SIP）在体外刺激血管内皮细胞迁移、增殖和毛细血管样管形成。尚不清楚S1 P是否刺激在组织缺血下诱导的体内血管生成。我们研究了外源性和内源性过度产生的SIP对小鼠后肢缺血后血管生成的影响。方法和结果局部注射S1 P对经历股动脉切除术的小鼠缺血后肢的血流恢复、血管生成和血管通透性的影响分别通过激光多普勒血流（LDBF）分析、抗CD 31免疫组织化学和Miles测定来评估。并与成纤维细胞生长因子（FGF）-2诱导的细胞凋亡进行比较。还评估了内源性过度产生SIP的鞘氨醇激酶1转基因小鼠的血流恢复和血管生成，并与野生型小鼠进行了比较。LDBF分析表明，每日肌内注射S1 P剂量依赖性地刺激血流恢复，与溶剂对照相比，血流量高达2倍，同时毛细血管密度增加1.7倍。最佳S1 P效果与用FGF-2获得的效果相当。注射S1 P不增加血管通透性。鞘氨醇激酶1转基因小鼠中缺血后血流恢复和血管生成加速，其显示出比野生型（WT）小鼠高40倍的鞘氨醇激酶活性和高1.8倍的骨骼肌中SIP含量，结论这些结果表明局部外源性SIP给药或内源性SIP过度产生促进了血管通透性的增加，缺血后血管生成和血流恢复。这些观察结果表明SIP对组织缺血的潜在治疗有用性。
Aims The lysophospholipid mediator sphingosine-1-phosphate(SIP) acts on vascular endothelial cells to stimulate migration, proliferation, and capillary-like tube formation in vitro. It is unknown whether S1P stimulates in vivo angiogenesis induced under tissue ischaemia. We investigated the effects of both exogenously and endogenously overproduced SIP on post-ischaemic angiogenesis in murine hindlimbs.Methods and results The effects of locally injected S1P on blood flow recovery, angiogenesis, and vascular permeability in mouse ischaemic hindlimbs that underwent femora[ arteriectomy were assessed by a laser Doppler blood flow (LDBF) analysis, anti-CD31 immunohistochemistry, and Miles assay, respectively, and compared with those induced by fibroblast growth factor (FGF)-2. Blood flow recovery and angiogenesis in sphingosine kinase 1-transgenic mice that overproduce SIP endogenously were also assessed and compared with wild-type mice. The LDBF analysis showed that daily intramuscular administration of S1P dose-dependently stimulated blood flow recovery, resulting in up to twice as much blood flow when compared with vehicle control, which was accompanied by 1.7-fold increase in the capillary density. The optimal S1P effects were comparable with those obtained with FGF-2. S1P injection did not increase vascular permeability. The post-ischaemic blood flow recovery and angiogenesis were accelerated in sphingosine kinase 1-transgenic mice, which showed 40-fold higher sphingosine kinase activity and 1.8-fold higher SIP content in skeletal muscle than in wild-type (WT) mice, without an increase in the vascular permeability when compared with WT mice.Conclusion These results indicate that either local exogenous SIP administration or endogenous SIP overproduction promotes post-ischaemic angiogenesis and blood flow recovery. These observations suggest potential therapeutic usefulness of SIP for tissue ischaemia.