Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization.
Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization.
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DOI：
10.1016/j.exer.2008.07.012
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发表时间：
2009-03
影响因子：
3.4
通讯作者：
Grant, Maria B.
中科院分区：
文献类型：
--
作者：
Caballero, Sergio;Swaney, James;Moreno, Kelli;Afzal, Aqeela;Kielczewski, Jennifer;Stoller, Glenn;Cavalli, Amy;Garland, William;Hansen, Genevieve;Sabbadini, Roger;Grant, Maria B.
关键词：
使用体外和体内血管生成模型测试了中和促血管生成介质 1-磷酸鞘氨醇 (S1P) 的新型单克隆抗体的功效，包括激光破坏布鲁赫膜诱导的脉络膜新生血管 (CNV)。通过半定量PCR检测人脑脉络丛内皮细胞（CPEC）、人肺微血管内皮细胞、人视网膜血管内皮细胞和循环内皮祖细胞中的S1P受体水平。评估了鼠或人源化抗 S1P 单克隆抗体 (mAb) 通过基质胶上的 CPEC 抑制 S1P 介导的微血管形成的能力，并在抗 S1P 治疗后测定了负载生长因子的基质胶塞中的毛细血管密度。 S1P 促进 CPEC 中的体外毛细管形成，这与这些细胞表达同源 S1P1-5 受体一致，并且 S1P 抗体诱导微血管形成的剂量依赖性减少。在激光诱导布鲁赫膜破裂的小鼠模型中，在接受激光损伤的小鼠后杯中检测到 S1P，但在未受伤的对照组中未检测到。在所有治疗组中，玻璃体内注射抗 S1P mAb 均显着抑制 CNV 形成和视网膜下胶原沉积（与对照组相比，p < 0.05），从而确定 S1P 是该模型中以前未被识别的血管生成和视网膜下纤维化的介质。这些研究结果表明，用抗 S1P mAb 中和 S1P 可能是一种通过减少血管生成和视网膜下纤维化来治疗渗出性年龄相关性黄斑变性患者的新方法，而血管生成和视网膜下纤维化是导致这种疾病视力丧失的原因。
The efficacy of novel monoclonal antibodies that neutralize the pro-angiogenic mediator, sphingosine-1-phosphate (S1P), were tested using in vitro and in vivo angiogenesis models, including choroidal neovascularization (CNV) induced by laser disruption of Bruch’s membrane. S1P receptor levels in human brain choroid plexus endothelial cells (CPEC), human lung microvascular endothelial cells, human retinal vascular endothelial cells, and circulating endothelial progenitor cells were examined by semi-quantitative PCR. The ability of murine or humanized anti-S1P monoclonal antibodies (mAbs) to inhibit S1P-mediated microvessel tube formation by CPEC on Matrigel was evaluated and capillary density in subcutaneous growth factor-loaded Matrigel plugs was determined following anti-S1P treatment. S1P promoted in vitro capillary tube formation in CPEC consistent with the presence of cognate S1P1–5 receptor expression by these cells and the S1P antibody induced a dose-dependent reduction in microvessel tube formation. In a murine model of laser-induced rupture of Bruch’s membrane, S1P was detected in posterior cups of mice receiving laser injury, but not in uninjured controls. Intravitreous injection of anti-S1P mAbs dramatically inhibited CNV formation and sub-retinal collagen deposition in all treatment groups (p < 0.05 compared to controls), thereby identifying S1P as a previously unrecognized mediator of angiogenesis and subretinal fibrosis in this model. These findings suggest that neutralizing S1P with anti-S1P mAbs may be a novel method of treating patients with exudative age-related macular degeneration by reducing angiogenesis and sub-retinal fibrosis, which are responsible for visual acuity loss in this disease.
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鞘氨醇激酶表达会增加细胞内鞘氨醇1-磷酸盐，并促进细胞生长和存活。
DOI：
10.1083/jcb.147.3.545
发表时间：
1999-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Olivera A;Kohama T;Edsall L;Nava V;Cuvillier O;Poulton S;Spiegel S
通讯作者：
Spiegel S
影响因子：
7.7
作者：
Caballero, Sergio;Sengupta, Nilanjana;Grant, Maria B.
通讯作者：
Grant, Maria B.
影响因子：
4
作者：
Bernatchez, PN;Tremblay, F;Sirois, MG
通讯作者：
Sirois, MG
DOI：
10.1152/ajpcell.2000.278.3.c612
发表时间：
2000-03-01
影响因子：
5.5
作者：
Lee, H;Goetzl, EJ;An, SZ
通讯作者：
An, SZ
影响因子：
56.9
作者：
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通讯作者：
Spiegel, S