Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.
Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.
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DOI：
10.1038/ncomms8893
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发表时间：
2015-08-05
影响因子：
16.6
通讯作者：
Sanchez T
中科院分区：
文献类型：
--
作者：
Kim GS;Yang L;Zhang G;Zhao H;Selim M;McCullough LD;Kluk MJ;Sanchez T
目前卒中再灌注治疗的使用和有效性受到再灌注损伤并发症的限制，这些并发症包括脑血管通透性增加和出血性转化。鞘氨醇-1-磷酸(S1P)是一种通过其受体(S1PR)有效调节血管完整性的物质。通过遗传学方法和S1PR2拮抗剂(JTE013)，我们证明了S1PR2在实验性卒中脑血管通透性的诱导、脑出血的发生和神经血管损伤中起关键作用。此外，抑制S1PR2还导致体内基质金属蛋白酶-9活性降低，脑微血管明胶酶活性降低。S1PR2免疫阳性仅在野生型小鼠的缺血微血管和人脑尸检标本的脑血管内皮细胞中检测到。在体外，S1PR2可以有效地调节脑内皮细胞对缺血和炎性损伤的反应。这一新途径的治疗靶向可能对中风患者具有重要的翻译相关性。鞘磷脂-1-磷酸鞘氨醇(S1P)通过与其受体S1PR1-5相互作用，在血管内稳态中发挥重要作用。在这里，通过使用遗传学和药理学方法，作者表明S1PR2介导的信号在小鼠中风模型中脑血管完整性的破坏和脑内出血的发展中起着至关重要的作用。
The use and effectiveness of current stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in experimental stroke. In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels. S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples. In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury. Therapeutic targeting of this novel pathway could have important translational relevance to stroke patients. The sphingolipid sphingosine-1-phosphate (S1P) plays a vital role in vascular homeostasis through the interaction with its receptors S1PR1-5. Here, by using genetic and pharmacological approaches, the authors show that S1PR2-mediated signaling is crucial for the disruption of cerebrovascular integrity and development of intracerebral haemorrhage in a mouse stroke model.