Blood-brain barrier breakdown in acute and chronic cerebrovascular disease - PubMed (original) (raw)

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Blood-brain barrier breakdown in acute and chronic cerebrovascular disease

Yi Yang et al. Stroke. 2011 Nov.

Abstract

Disruptions of the blood-brain barrier (BBB) and edema formation both play key roles in the development of neurological dysfunction in acute and chronic cerebral ischemia. Animal studies have revealed the molecular cascades that are initiated with hypoxia/ischemia in the cells forming the neurovascular unit and that contribute to cell death. Matrix metalloproteinases cause reversible degradation of tight junction proteins early after the onset of ischemia, and a delayed secondary opening during a neuroinflammatory response occurring from 24 to 72 hours after. Cyclooxygenases are important in the delayed opening as the neuroinflammatory response progresses. An early opening of the BBB within the 3-hour therapeutic window for tissue-type plasminogen activator can allow it to enter the brain and increase the risk of hemorrhage. Chronic hypoxic hypoperfusion opens the BBB, which contributes to the cognitive changes seen with lacunar strokes and white matter injury in subcortical ischemic vascular disease. This review will describe the molecular and cellular events associated with BBB disruption and potential therapies directed toward restoring the integrity of the neurovascular unit.

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Figures

Fig. 1

Fig. 1

Mechanism for MMP-mediated BBB disruption in hypoxia/ischemia. Induction of hypoxia inducible factor-α (HIF-α) by loss of oxygen and ATP leads to activation of MMP-2. The constitutive enzyme, proMT1-MMP, is activated by the convertase, Furin, and it activates proMMP-2. Secondary neuroinflammation with the formation of cytokines (TNF-α and IL-1β) and induction of MMP-9 and -3 occurs. ProMMP-9 is activated by MMP-3 and free radicals. Active MMPs degrade the basal lamina and tight junctions of endothelial cells, thereby opening the blood–brain barrier (BBB). Opening of the BBB leads to vasogenic edema.

Fig. 2

Fig. 2

Schematic drawing to show the theoretical mechanisms leading to the initial reversible opening of the BBB and the later more slowly irreversible opening. Reperfusion injury leads to a biphasic opening of the BBB. The early opening occurs several hours after the onset of reperfusion due to activation of the constitutive enzyme gelatinase A (MMP-2). This initial opening is transient and reversible. At 24 to 72 hours later, the inflammatory response leads to the induction of MMP-3 and MMP-9, which induce more intense and irreversible damage to the blood vessel.

Fig. 3

Fig. 3

Evidence of HARM for a representative acute stroke patient with early blood–brain barrier (BBB) disruption (woman, 81 years old, baseline NIHSS 17, no tPA). Left: FLAIR pre-Gd contrast, Middle: FLAIR post-Gd contrast, Left: isotropic DWI (b =1000). FLAIR enhancement was never seen before Gd contrast. After Gd contrast, FLAIR images were positive for HARM. (permission pending)

Fig. 4

Fig. 4

Two subcortical ischemic vascular disease (SIVD) patients with white matter hyperintensities (WMHs). A) FLAIR MRI shows WMHs in the centrum semiovale (arrowhead) without involvement of the cortex. B) The corresponding permeability map has regions of moderately increased permeability (light blue) and high permeability (red). C) FLAIR image from another SIVD patient with larger white matter lesions (arrowhead). D) Permeability map shows increased permeability is limited to two small regions within the WMHs.

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References

    1. Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10:1369–1376. - PubMed
    1. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. PharmacolRev. 2005;57:173–185. - PubMed
    1. Milner R, Hung S, Wang X, Berg GI, Spatz M, del Zoppo GJ. Responses of endothelial cell and astrocyte matrix-integrin receptors to ischemia mimic those observed in the neurovascular unit. Stroke. 2008;39:191–197. - PMC - PubMed
    1. Dore-Duffy P. Pericytes: Pluripotent cells of the blood brain barrier. Curr Pharm Des. 2008;14:1581–1593. - PubMed
    1. Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010;468:562–566. - PMC - PubMed

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