Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein

被引:455
作者
Yepes, M
Sandkvist, M
Moore, EG
Bugge, TH
Strickland, DK
Lawrence, DA
机构
[1] Amer Red Cross, Holland Lab, Vasc Biol Dept, Rockville, MD 20855 USA
[2] Georgetown Univ Hosp, Dept Neurol, Washington, DC 20007 USA
[3] Amer Red Cross, Holland Lab, Dept Biochem, Rockville, MD 20855 USA
[4] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA
关键词
D O I
10.1172/JCI200319212
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1533 / 1540
页数:8
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