Kim Gab Seok, Yang Li, Zhang Guoqi, Zhao Honggang, Selim Magdy, McCullough Louise D, Kluk Michael J, Sanchez Teresa
Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nat Commun. 2015 Aug 5;6:7893. doi: 10.1038/ncomms8893.
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.
目前的中风再灌注疗法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)正作为一种通过其受体(S1PR)调节血管完整性的强效调节剂而崭露头角。通过使用基因方法和一种S1PR2拮抗剂(JTE013),我们在此表明S1PR2在实验性中风中诱导脑血管通透性、脑出血的发生和神经血管损伤方面起着关键作用。此外,抑制S1PR2会导致体内基质金属蛋白酶(MMP)-9活性降低以及脑微血管中的明胶酶活性降低。仅在野生型小鼠的缺血微血管和人脑尸检样本的脑血管内皮中检测到S1PR2免疫阳性。在体外,S1PR2有力地调节脑内皮对缺血和炎性损伤的反应。对这一新途径进行治疗性靶向可能对中风患者具有重要的转化意义。