Su Enming J, Fredriksson Linda, Geyer Melissa, Folestad Erika, Cale Jacqueline, Andrae Johanna, Gao Yamei, Pietras Kristian, Mann Kris, Yepes Manuel, Strickland Dudley K, Betsholtz Christer, Eriksson Ulf, Lawrence Daniel A
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor Michigan 48109-0644, USA.
Nat Med. 2008 Jul;14(7):731-7. doi: 10.1038/nm1787. Epub 2008 Jun 22.
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.
由于对出血性并发症的担忧以及要求在症状出现后3小时内给予组织型纤溶酶原激活剂（tPA），缺血性中风的tPA溶栓治疗受到明显限制。在此我们报告，tPA激活潜在的血小板衍生生长因子CC（PDGF-CC）可能解释了这些限制。在无缺血的情况下，脑室内注射tPA或活性PDGF-CC会导致脑血管通透性显著增加。相反，将抗PDGF-CC中和抗体与tPA共同注射可阻断这种通透性增加，表明PDGF-CC是神经血管单元内tPA的下游底物。这些效应是通过激活血管周围星形胶质细胞上的血小板衍生生长因子α受体（PDGFR-α）介导的，缺血性中风后用PDGFR-α拮抗剂伊马替尼治疗小鼠可降低与溶栓tPA延迟给药相关的脑血管通透性和出血性并发症。这些数据表明，PDGF信号传导调节血脑屏障通透性，并提示了中风治疗的潜在新策略。
