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Endogenous defence mechanisms by which the brain protects itself against noxious stimuli and recovers from ischaemic damage are a key target of stroke research. The loss of viable brain tissue in the ischaemic core region after stroke is associated with damage to the surrounding area known as the penumbra. Activation of the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the cellular defence against oxidative stress via transcriptional upregulation of phase II defence enzymes and antioxidant stress proteins. Although recent evidence implicates Nrf2 in neuroprotection, it is not known whether activation of this pathway within the neurovascular unit protects the brain against blood-brain barrier breakdown and cerebrovascular inflammation. Targeting the neurovascular unit should provide novel insights for effective treatment strategies and facilitate translation of experimental findings into clinical therapy. This review focuses on the cytoprotective role of Nrf2 in stroke and examines the evidence that the Nrf2-Keap1 defence pathway may serve as a therapeutic target for neurovascular protection. Abbreviations ARE, antioxidant response element; DHA, dehydroascorbate; GSH, glutathione; HO-1, haem oxygenase-1; Keap1, Kelch-like ECH-associated protein 1; MCAO, middle cerebral artery occlusion; Nrf2, nuclear factor erythroid 2-related factor 2; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; ROS, reactive oxygen species; tBHQ, tert-butylhydroquinone; Trx, thioredoxin.

SummaryThe vascular endothelium operates in a highly polarized environment, but to date there has been little exploration of apicobasal polarization of its signaling. We show that VEGF-A, histamine, IGFBP3, and LPA trigger unequal endothelial responses when acting from the circulation or the parenchymal side at blood-neural barriers. For VEGF-A, highly polarized receptor distribution contributed to distinct signaling patterns: VEGFR2, which was found to be predominantly abluminal, mediated increased permeability via p38; in contrast, luminal VEGFR1 led to Akt activation and facilitated cytoprotection. Importantly, such differential apicobasal signaling and VEGFR distribution were found in the microvasculature of brain and retina but not lung, indicating that endothelial cells at blood-neural barriers possess specialized signaling compartments that assign different functions depending on whether an agonist is tissue or blood borne.

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1. Permeability of pial venular capillaries to Lucifer Yellow (PLY) was measured using the single microvessel occlusion technique. 2. PLY was extremely low, when measured shortly after the removal of the meninges, consistent with an intact blood-brain barrier, but rose spontaneously to (1·65 ± 0·60) ² 10¦É cm s¢ (mean ± s.d.) within 20-60 min. This first phase of spontaneous disruption lasted 44-164 min. A second phase started when PLY rose sharply, and was characterized by rapid permeability fluctuations with a mean of (12·31 ± 15·14) ² 10¦É cm s¢. 3. The first phase could be mimicked by applying the divalent cation ionophore A23187 in the presence of Ca¥, when PLY rose by (1·47 ± 0·25) ² 10¦É cm s¢ (mean ± s.e.m.). Application of histamine (10 ìÒ) to tight vessels increased PLY by (2·41 ± 0·22) ² 10¦É cm s¢. 4. Substances that raised intraendothelial cAMP of vessels during the first phase of disruption reduced PLY to the initial blood-brain barrier level. 5. The second phase could be prevented by applying catalase. Similar high and fluctuating PLY values could be produced reversibly by applying arachidonic acid or NHÚCl. 6. This is the first report of two distinct types of permeability increase in the cerebral microvasculature, and reasons for this are discussed.

Acute activation of NADPH oxidase by phospholipase C-mediated activation of Ca(2+)-dependent PKC occurs downstream of RAGE activation to acutely increase retinal capillary permeability in the isolated perfused rat retina.