Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA, USA.
Department of Neurology & Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA.
J Cereb Blood Flow Metab. 2022 Apr;42(4):667-682. doi: 10.1177/0271678X211060395. Epub 2021 Nov 19.
Ischemic tolerance is a phenomenon whereby transient exposure to a non-injurious preconditioning stimulus triggers resistance to a subsequent lethal ischemic insult. Despite the fact that not only neurons but also astrocytes and endothelial cells have a unique response to preconditioning stimuli, current research has been focused mostly on the effect of preconditioning on neuronal death. Thus, it is unclear if the blood-brain barrier (BBB) can be preconditioned independently of an effect on neuronal survival. The release of tissue-type plasminogen activator (tPA) from perivascular astrocytes in response to an ischemic insult increases the permeability of the BBB. In line with these observations, treatment with recombinant tPA increases the permeability of the BBB and genetic deficiency of tPA attenuates the development of post-ischemic edema. Here we show that tPA induces ischemic tolerance in the BBB independently of an effect on neuronal survival. We found that tPA renders the BBB resistant to an ischemic injury by inducing TNF-α-mediated astrocytic activation and increasing the abundance of aquaporin-4-immunoreactive astrocytic end-feet processes in the neurovascular unit. This is a new role for tPA, that does not require plasmin generation, and with potential therapeutic implications for patients with cerebrovascular disease.
缺血耐受是一种现象，即短暂暴露于非损伤性预处理刺激会引发对随后致命性缺血性损伤的抵抗。尽管不仅神经元，而且星形胶质细胞和内皮细胞对预处理刺激有独特的反应，但目前的研究主要集中在预处理对神经元死亡的影响上。因此，目前尚不清楚血脑屏障 (BBB) 是否可以在不影响神经元存活的情况下进行预处理。血管周星形胶质细胞对缺血性损伤的反应释放组织型纤溶酶原激活物 (tPA)，增加 BBB 的通透性。与这些观察结果一致，用重组 tPA 治疗会增加 BBB 的通透性，而 tPA 的基因缺失会减弱缺血后水肿的发展。在这里，我们表明 tPA 通过诱导 TNF-α 介导的星形胶质细胞激活和增加神经血管单元中水通道蛋白 4 免疫反应性星形胶质细胞终足过程的丰度，独立于对神经元存活的影响，诱导 BBB 产生缺血耐受。这是 tPA 的一个新作用，不需要纤溶酶的产生，对脑血管疾病患者具有潜在的治疗意义。
