Yepes Manuel, Sandkvist Maria, Moore Elizabeth G, Bugge Thomas H, Strickland Dudley K, Lawrence Daniel A
Department of Vascular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
J Clin Invest. 2003 Nov;112(10):1533-40. doi: 10.1172/JCI19212.
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.
脑血管通透性的调节对于正常的脑内环境稳定至关重要，血脑屏障（BBB）的“破坏”与多种神经系统疾病中血管源性水肿和颅内高压的发生有关。在本研究中，我们证明脑缺血后血管周围组织内源性组织型纤溶酶原激活剂（tPA）活性增加通过一种独立于纤溶酶原（Plg）和基质金属蛋白酶-9（MMP-9）的机制诱导血脑屏障开放。我们还表明，在无缺血情况下向脑脊液中注射tPA会导致血管通透性迅速出现剂量依赖性增加。尿激酶型纤溶酶原激活剂（uPA）未出现这种活性，但在Plg基因敲除小鼠中可诱导该活性，证实该效应不依赖于Plg。然而，该活性被抗低密度脂蛋白受体相关蛋白（LRP）抗体和LRP拮抗剂受体相关蛋白（RAP）阻断，提示这是一个受体介导的过程。这些研究共同表明，tPA在血脑屏障开放的早期阶段直接增加血管通透性方面既是必要的也是充分的，并提示这是通过受体介导的细胞信号事件发生的，而不是通过血管基底膜的普遍降解。
