Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein
Manuel Yepes, … , Dudley K. Strickland, Daniel A. Lawrence
Manuel Yepes, … , Dudley K. Strickland, Daniel A. Lawrence
Published November 15, 2003
Citation Information: J Clin Invest. 2003;112(10):1533-1540. https://doi.org/10.1172/JCI19212.
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Article Neuroscience

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

Abstract

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.

Authors

Manuel Yepes, Maria Sandkvist, Elizabeth G. Moore, Thomas H. Bugge, Dudley K. Strickland, Daniel A. Lawrence

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Figure 2

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BBB permeability following cerebral ischemia. (a) Analysis of Evans blue...
BBB permeability following cerebral ischemia. (a) Analysis of Evans blue dye extravasation in mice. Brains were removed and photographed 6 hours after MCAO. All images are ipsilateral to the ischemic area. WT ipsilateral is a WT C57BL/6J mouse, and WT + Ns is a WT C57BL/6J mouse treated with an intraventricular injection of 2.5 μl of 16 μM neuroserpin immediately after MCAO. tPA–/–, uPA–/–, Plg–/–, and MMP9–/– are mice deficient in the enzyme indicated. The arrows indicate the area of Evans blue extravasation associated with the ischemic injury. (b) Quantitative analysis of Evans blue extravasation from brain extracts 6 hours after MCAO. Sham indicates animals subjected to all procedures except MCA ligation. The results represent the specific absorbance of Evans blue at 620 nm calculated as percentage of that of the WT control, either C57BL/6J (C57) or 129S6/SvEv as described in Methods. As a control for perfusion efficiency, the absorbance of the contralateral hemisphere was subtracted from that of the hemisphere ipsilateral to the MCAO. For each condition, n = 4. *P < 0.05 relative to WT control mice receiving MCAO.