Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina
Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina
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DOI：
10.1172/jci31123
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Hla, Timothy
中科院分区：
文献类型：
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作者：
Skoura, Athanasia;Sanchez, Teresa;Hla, Timothy
1-磷酸鞘氨醇（S1 P）是一种多功能脂质介质，通过G蛋白偶联受体（S1 PR）的S1 P家族发出信号，调节血管成熟、渗透性和血管生成。本研究探讨了SIP 2受体（S1 P（2）R）在小鼠视网膜正常血管生成和缺氧诱导的病理性血管生成中的作用。缺氧应激时，内皮细胞S1 P（2）R表达增强。当新生小鼠经受缺血驱动的视网膜病变时，S1 p2（-/-）小鼠玻璃体腔中的病理性新生血管形成受到抑制，同时内皮间隙和炎性细胞浸润减少。此外，EC图案和正常的血管重建到视网膜的无血管区得到增强。在S1 p2（-/-）小鼠视网膜中观察到促炎酶环氧合酶-2（考克斯-2）的表达减少和eNOS的表达增加。内皮细胞S1 P（2）R的激活可诱导考克斯-2的表达，并抑制eNOS的表达。这些数据表明，S1 P（2）R驱动的炎症过程是病理性视网膜血管生成中的重要分子事件。我们认为，拮抗S1 P（2）R可能是预防和/或治疗病理性眼部新生血管的一种新的治疗方法。
Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein-coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of SIP 2 receptor (S1P(2)R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P(2)R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2(-/-) mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2(-/-) mouse retina. S1P(2)R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P(2)R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P(2)R maybe a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization.