Cerebral endothelial expression of Robo1 affects brain infiltration of polymorphonuclear neutrophils during mouse stroke recovery

Gangaraju, Sandhya; Sultan, Khadeejah T.; Whitehead, Shawn N.; Nilchi, Ladan; Slinn, Jacqueline; Li, Xuesheng; Hou, Sheng T.

doi:10.1016/j.nbd.2013.02.014

Cited by 10 publications

(6 citation statements)

References 22 publications

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“…To determine the mechanisms underlying Sema3A-induced vascular permeability,we used RBEC cultured on transwell to determine the permeability of fluorescent-labeledGr1 positive polymorphonuclear neurtrophils (PMNs). This assay is a powerful tool to investigate mechanisms of BBB permeability 51 . Indeed, as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

Hou

Nilchi

et al. 2015

Sci Rep

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Semaphorin 3A (Sema3A) increased significantly in mouse brain following cerebral ischemia. However, the role of Sema3A in stroke brain remains unknown. Our aim was to determine wether Sema3A functions as a vascular permeability factor and contributes to ischemic brain damage. Recombinant Sema3A injected intradermally to mouse skin, or stereotactically into the cerebral cortex, caused dose- and time-dependent increases in vascular permeability, with a degree comparable to that caused by injection of a known vascular permeability factor vascular endothelial growth factor receptors (VEGF). Application of Sema3A to cultured endothelial cells caused disorganization of F-actin stress fibre bundles and increased endothelial monolayer permeability, confirming Sema3A as a permeability factor. Sema3A-mediated F-actin changes in endothelial cells were through binding to the neuropilin2/VEGFR1 receptor complex, which in turn directly activates Mical2, a F-actin modulator. Down-regulation of Mical2, using specific siRNA, alleviated Sema3A-induced F-actin disorganization, cellular morphology changes and endothelial permeability. Importantly, ablation of Sema3A expression, cerebrovascular permeability and brain damage were significantly reduced in response to transient middle cerebral artery occlusion (tMCAO) and in a mouse model of cerebral ischemia/haemorrhagic transformation. Together, these studies demonstrated that Sema3A is a key mediator of cerebrovascular permeability and contributes to brain damage caused by cerebral ischemia.

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Section: Resultsmentioning

confidence: 99%

Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

Hou

Nilchi

et al. 2015

Sci Rep

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“…Slit1 is expressed on neutrophils and prevents infiltration across cerebral endothelial cells through interactions with Robo1. 63 After ischemic stroke, there is a transient reduction in Robo1 expression that permits infiltration of Slit1 expressing neutrophils into brain. 63 Neutrophils that transmigrate into the central nervous system (CNS) via IL-1 may promote CNS injury and neurotoxicity through the release of NETs.…”

Section: Targeting Neutrophil Transmigration and Neurovascular Interamentioning

confidence: 99%

“…63 After ischemic stroke, there is a transient reduction in Robo1 expression that permits infiltration of Slit1 expressing neutrophils into brain. 63 Neutrophils that transmigrate into the central nervous system (CNS) via IL-1 may promote CNS injury and neurotoxicity through the release of NETs. 64 The above studies imply that blocking neutrophil transmigration across injured vessel walls after ischemic stroke may improve outcomes after stroke.…”

Section: Targeting Neutrophil Transmigration and Neurovascular Interamentioning

confidence: 99%

Targeting Neutrophils in Ischemic Stroke: Translational Insights from Experimental Studies

Jickling

Liu

Ander

et al. 2015

J Cereb Blood Flow Metab

477

434

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Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke. After stroke, neutrophils respond rapidly promoting blood-brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules. In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required. Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions.

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“…Transient and focal MCAO was induced in male mice (8-10 weeks old, 25-30 g of body weight) by intraluminal occlusion of the left middle cerebral artery (MCA), as we previously described. 21 Briefly, mice were anesthetized with 1.5% isoflurane in air and an 8-0 monofilament with a silicon-coated tip was inserted into the carotid artery to block the blood flow into the MCA. The body temperature of mice was maintained at 37 AE 0.5 C during surgery utilizing a heating pad.…”

Section: Transient Mcao Model In Micementioning

confidence: 99%

Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity

Zhang,

Zhao,

Sha

et al. 2023

J Cereb Blood Flow Metab

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Cerebral vasogenic edema, a severe complication of ischemic stroke, aggravates neurological deficits. However, therapeutics to reduce cerebral edema still represent a significant unmet medical need. Brain microvascular endothelial cells (BMECs), vital for maintaining the blood-brain barrier (BBB), represent the first defense barrier for vasogenic edema. Here, we analyzed the proteomic profiles of the cultured mouse BMECs during oxygen-glucose deprivation and reperfusion (OGD/R). Besides the extensively altered cytoskeletal proteins, ephrin type-A receptor 4 (EphA4) expressions and its activated phosphorylated form p-EphA4 were significantly increased. Blocking EphA4 using EphA4-Fc, a specific and well-tolerated inhibitor shown in our ongoing human phase I trial, effectively reduced OGD/R-induced BMECs contraction and tight junction damage. EphA4-Fc did not protect OGD/R-induced neuronal and astrocytic death. However, administration of EphA4-Fc, before or after the onset of transient middle cerebral artery occlusion (tMCAO), reduced brain edema by about 50%, leading to improved neurological function recovery. The BBB permeability test also confirmed that cerebral BBB integrity was well maintained in tMCAO brains treated with EphA4-Fc. Therefore, EphA4 was critical in signaling BMECs-mediated BBB breakdown and vasogenic edema during cerebral ischemia. EphA4-Fc is promising for the treatment of clinical post-stroke edema.

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Cerebral endothelial expression of Robo1 affects brain infiltration of polymorphonuclear neutrophils during mouse stroke recovery

Cited by 10 publications

References 22 publications

Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

Targeting Neutrophils in Ischemic Stroke: Translational Insights from Experimental Studies

Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity

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