Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke
Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke
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DOI：
10.1038/nm1787
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发表时间：
2008-07-01
期刊：
影响因子：
82.9
通讯作者：
Lawrence, Daniel A.
中科院分区：
文献类型：
--
作者：
Su, Enming J.;Fredriksson, Linda;Lawrence, Daniel A.
组织型纤溶酶原激活剂（tPA）对缺血性卒中的溶栓治疗明显受到限制，因为担心出血并发症和tPA在出现症状后3小时内给予的要求。在这里，我们报告tPA激活潜在血小板衍生生长因子- cc （PDGF-CC）可能解释了这些局限性。在没有缺血的情况下，脑室内注射tPA或活性PDGF-CC可导致脑血管通透性显著增加。相反，PDGF-CC中和抗体与tPA共同注射可阻断这种增加的渗透性，表明PDGF-CC是神经血管单位内tPA的下游底物。这些作用是通过激活血管周围星形胶质细胞上的pdgf - α受体（pdgfr - α）介导的，并且在缺血性卒中后用pdgfr - α拮抗剂伊马替尼治疗小鼠可以降低脑血管通透性和与溶栓tPA晚期给药相关的出血并发症。这些数据表明PDGF信号调节血脑屏障的通透性，并为中风治疗提供了潜在的新策略。
Thrombolytic treatment of ischemic stroke with tissue plasminogen activator (tPA) is markedly limited owing to concerns about hemorrhagic complications and the requirement that tPA be administered within 3 h of symptoms. Here we report that tPA activation of latent platelet-derived growth factor-CC (PDGF-CC) may explain these limitations. Intraventricular injection of tPA or active PDGF-CC, in the absence of ischemia, leads to significant increases in cerebrovascular permeability. In contrast, co-injection of neutralizing antibodies to PDGF-CC with tPA blocks this increased permeability, indicating that PDGF-CC is a downstream substrate of tPA within the neurovascular unit. These effects are mediated through activation of PDGF-alpha receptors (PDGFR-alpha) on perivascular astrocytes, and treatment of mice with the PDGFR-alpha antagonist imatinib after ischemic stroke reduces both cerebrovascular permeability and hemorrhagic complications associated with late administration of thrombolytic tPA. These data demonstrate that PDGF signaling regulates blood-brain barrier permeability and suggest potential new strategies for stroke treatment.