Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein
Manuel Yepes, Maria Sandkvist, Elizabeth G. Moore, Thomas H. Bugge, Dudley K. Strickland, Daniel A. Lawrence
Manuel Yepes, Maria Sandkvist, Elizabeth G. Moore, Thomas H. Bugge, Dudley K. Strickland, Daniel A. Lawrence
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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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Temporal and spatial relationship between tPA activity and vascular perm...
Temporal and spatial relationship between tPA activity and vascular permeability following MCAO in WT (C57BL/6J) mice. In a–d, tPA activity 1 hour after MCAO is shown in red by in situ zymography, and cell nuclei are in blue (DAPI). (a) By 1 hour after MCAO there is significant tPA activity in the vessel wall and in the perivascular tissue surrounding a vessel bordering the necrotic area. (b and c) The same vessel in adjacent sections (5 μm), but with anti-tPA antibodies included (b), or without the addition of Plg (c) in the overlay. (d) The background tPA activity associated with a vessel in a corresponding area in the contralateral hemisphere from the same section shown in a. In a–d the original magnification was ×100. (e–h) Evans blue extravasation is shown in red and cell nuclei in blue (DAPI) 6 hours after MCAO. (e) A low-magnification view of the entire ischemic area. (f) Evans blue extravasation from a vessel located in the area adjacent to the ischemic area, similar to the one seen in a. (g) Electronic magnification of the box in f. The arrow indicates an area of Evans blue leakage outside the internal elastic lamina of the vessel. (h) Evans blue is shown adhering to the vessel wall, but no extravasation is seen in a vessel from the same section seen in f and g but located in the corresponding region of the contralateral hemisphere. Ipsi, ipsilateral; Contra, contralateral.