Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment.
Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment.
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DOI：
10.1161/strokeaha.117.018334
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发表时间：
2017-12
期刊：
影响因子：
8.3
通讯作者：
Kuan CY
中科院分区：
文献类型：
--
作者：
Sun YY;Lee J;Huang H;Wagner MB;Joiner CH;Archer DR;Kuan CY
溶解性卒中治疗对镰状细胞性贫血（SCA）患者的影响尚不清楚，尽管最近的一项研究表明，共存的SCA不会增加脑出血的风险。这一发现要求对溶栓治疗中风的效果进行系统分析，首先在人源化镰状小鼠中，然后在患者中。还需要SCA相关血管病变的其他预测标志物。我们使用多普勒超声检查Townes镰状小鼠的颈动脉，分别测试它们对3个月或6个月龄的反复轻度缺氧缺血（rmHI）和短暂缺氧缺血（tHI）诱导的中风的反应。我们还研究了组织纤溶酶原激活剂（tPA）治疗tHI损伤的镰状小鼠的影响。三个月大的SS小鼠显示颈动脉阻力指数（RI）升高，对rmHI诱导的脑梗死敏感性更高。六个月大的SS小鼠显示出更大的RI和增加的血流速度，而没有阻塞性血管病变的颈动脉。相反，SS小鼠的脑血管壁显示纤溶酶原激活物抑制剂-1（派-1）和P-选择素的异位表达，表明促粘附和促血栓形成倾向。事实上，SS小鼠表现出增强的白细胞和血小板粘附到脑血管壁，更广泛的纤维蛋白沉积，以及tHI后更高的死亡率。然而，tHI后用tPA治疗减少了SS小鼠的血栓形成和死亡率。镰状小鼠对缺氧/缺血诱导的脑梗死敏感，但从溶栓治疗中获益。颈动脉阻力指数增加可能是镰状细胞血管病变的早期标志。
The effects of lytic stroke therapy in patients with sickle cell anemia (SCA) are unknown, although a recent study suggested that co-existent SCA does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, then in patients. There is also a need for additional predictive markers of SCA-associated vasculopathy. We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive-mild hypoxia-ischemia (rmHI) and transient hypoxia-ischemia (tHI)-induced stroke at three or six months of age, respectively. We also examined the effects of tissue-plasminogen activator (tPA) treatment in tHI-injured sickle mice. Three-month-old SS mice showed elevated resistive index (RI) in the carotid artery and higher sensitivity to rmHI-induced cerebral infarct. Six-month-old SS mice showed greater RI and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of Plasminogen Activator Inhibitor-1 (PAI-1) and P-Selectin, suggesting a pro-adhesive and pro-thrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortality after tHI. Yet, post-tHI treatment with tPA reduced thrombosis and mortality in SS mice. Sickle mice are sensitive to hypoxia/ischemia-induced cerebral infarct, but benefit from thrombolytic treatment. An increased resistive index in carotid arteries may be an early marker of sickle cell vasculopathy.