PDGFR-β restores blood-brain barrier functions in a mouse model of focal cerebral ischemia

Although platelet-derived growth factor receptor beta (PDGFR-β) mediates the recruitment of vascular pericytes into ischemic lesion to restore the blood-brain barrier (BBB) dysfunction, its mechanisms still remain elusive . Compared with control PDGFR-βfloxed/floxed mice (Floxed), postnatally induced systemic PDGFR-β knockout mice (Esr-KO) not only showed severe brain edema, neurologic functional deficits, decreased expression of tight junction (TJ) proteins, abundant endothelial transcytosis, and deformed TJs in the BBB, but also showed reduced expression of transforming growth factor-β (TGF-β) protein after photothrombotic middle cerebral artery occlusion (MCAO). In endothelial-pericyte co-culture, an in vitro model of BBB, the increment in the barrier function of endothelial monolayer induced by pericyte co-culture was completely cancelled by silencing PDGFR-β gene expression in pericytes, and was additively improved by PDGFR-β and TGF-β receptor signals under hypoxia condition. Exogenous PDGF-BB increased the expression of p-Smad2/3, while anti-TGF-β1 antibody at least partially inhibited the phosphorylation of Smad2/3 after PDGF-BB treatment in vitro. Furthermore, pre-administration of TGF-β1 partially alleviated edema formation, neurologic dysfunction, and TJs reduction in Esr-KO mice after MCAO. Accordingly, PDGFR-β signalling, via TGF-β signalling, may be crucial for restoration of BBB integrity after cerebral ischemia and therefore represents a novel potential therapeutic target.

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Regulator of G‐Protein Signaling 5 Maintains Brain Endothelial Cell Function in Focal Cerebral Ischemia

Journal of the American Heart Association ◽

10.1161/jaha.120.017533 ◽

2020 ◽

Vol 9 (18) ◽

Author(s):

Nikola Sladojevic ◽

Brian Yu ◽

James K. Liao

Keyword(s):

Endothelial Cells ◽

Cerebral Ischemia ◽

G Protein ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Brain Barrier ◽

Stroke Severity ◽

Protein Signaling ◽

Blood Brain

Background Regulator of G‐protein signaling 5 (RGS5) is a negative modulator of G‐protein–coupled receptors. The role of RGS5 in brain endothelial cells is not known. We hypothesized that RGS5 in brain microvascular endothelial cells may be an important mediator of blood‐brain barrier function and stroke severity after focal cerebral ischemia. Methods and Results Using a transient middle cerebral artery occlusion model, we found that mice with global and endothelial‐specific deletion of Rgs5 exhibited larger cerebral infarct size, greater neurological motor deficits, and increased brain edema. In our in vitro models, we observed increased G q activity and elevated intracellular Ca 2+ levels in brain endothelial cells. Furthermore, the loss of endothelial RGS5 leads to decreased endothelial NO synthase expression and phosphorylation, relocalization of endothelial tight junction proteins, and increased cell permeability. Indeed, RGS5 deficiency leads to increased Rho‐associated kinase and myosin light chain kinase activity, which were partially reversed in our in vitro model by pharmacological inhibition of G q , metabotropic glutamate receptor 1, and ligand‐gated ionotropic glutamate receptor. Conclusions Our findings indicate that endothelial RGS5 plays a novel neuroprotective role in focal cerebral ischemia. Loss of endothelial RGS5 leads to hyperresponsiveness to glutamate signaling pathways, enhanced Rho‐associated kinase– and myosin light chain kinase–mediated actin‐cytoskeleton reorganization, endothelial dysfunction, tight junction protein relocalization, increased blood‐brain barrier permeability, and greater stroke severity. These findings suggest that preservation of endothelial RGS5 may be an important therapeutic strategy for maintaining blood‐brain barrier integrity and limiting the severity of ischemic stroke.

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Hyperbaric oxygen reduces blood-brain barrier damage and edema after transient focal cerebral ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9591524.0266 ◽

2005 ◽

Vol 25 (1_suppl) ◽

pp. S266-S266

Author(s):

Roland Veltkamp ◽

Li Sun ◽

Dirk A Siebing ◽

Katja Bieber ◽

Sabine Heiland ◽

...

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Hyperbaric Oxygen ◽

Focal Cerebral Ischemia ◽

Brain Barrier ◽

Blood Brain ◽

Transient Focal Cerebral Ischemia ◽

Blood Brain Barrier Damage

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Effects of blockade of ionotropic glutamate receptors on blood–brain barrier disruption in focal cerebral ischemia

Neurological Sciences ◽

10.1007/s10072-010-0241-5 ◽

2010 ◽

Vol 31 (6) ◽

pp. 699-703 ◽

Cited By ~ 15

Author(s):

Xia Liu ◽

Christine Hunter ◽

Harvey R. Weiss ◽

Oak Z. Chi

Keyword(s):

Cerebral Ischemia ◽

Glutamate Receptors ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Brain Barrier ◽

Ionotropic Glutamate Receptors ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption

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Early Appearance of Activated Matrix Metalloproteinase-9 after Focal Cerebral Ischemia in Mice: A Possible Role in Blood—Brain Barrier Dysfunction

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199909000-00010 ◽

1999 ◽

Vol 19 (9) ◽

pp. 1020-1028 ◽

Cited By ~ 301

Author(s):

Yvan Gasche ◽

Miki Fujimura ◽

Yuiko Morita-Fujimura ◽

Jean-Christophe Copin ◽

Makoto Kawase ◽

...

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Vasogenic Edema ◽

Tissue Inhibitor Of Metalloproteinase ◽

Brain Barrier ◽

Critical Event ◽

Secondary Brain Injury ◽

Blood Brain ◽

Bbb Permeability

During cerebral ischemia blood–brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly ( P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745,7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability, Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly ( P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.

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