Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein
Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein
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DOI：
10.1172/jci200319212
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发表时间：
2003-11-01
影响因子：
15.9
通讯作者：
Lawrence, DA
中科院分区：
文献类型：
--
作者：
Yepes, M;Sandkvist, M;Lawrence, DA
脑血管通透性的调节对正常的脑内环境平衡至关重要，而血脑屏障(BBB)的破坏与许多神经疾病中血管源性水肿和颅内高压的发展有关。在这项研究中，我们证明了脑缺血后血管周围组织内源性组织型纤溶酶原激活物(TPA)活性的增加通过一种独立于纤溶酶原(PLG)和基质金属蛋白酶-9的机制诱导血脑屏障的开放。我们还展示了脑脊液中注射tPA。在没有缺血的情况下，液体会导致血管通透性迅速增加，这是剂量依赖性的。这种活性在尿激酶型PLG激活剂(UPA)中看不到，但在PLG(-/-)小鼠中被诱导，证实其作用不依赖于PLG。然而，这种活性被低密度脂蛋白受体相关蛋白(LRP)的抗体和LRP拮抗剂受体相关蛋白(RAP)所阻断，这表明这是一个受体介导的过程。总之，这些研究表明，在血脑屏障开放的早期阶段，tPA是直接增加血管通透性的必要条件和充分条件，并表明这是通过受体介导的细胞信号事件而不是通过血管基底膜的普遍降解来实现的。
The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal. fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg(-/-) mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.