EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke

Okyere, Benjamin; Mills, William A.; Wang, Xia; Chen, Michael; Chen, Jiang; Hazy, Amanda; Qian, Yun; Matson, John B.; Theus, Michelle H.

doi:10.1172/jci131493

Cited by 33 publications

(43 citation statements)

References 62 publications

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“…Strong evidence supports the role of vascular-derived ephrin type-A receptor 4 (EphA4) in the regulation of hippocampal neurogenesis 30 , 31 . Our recent findings implicate EphA4 as critical player in cerebrovascular function 32 – 34 . EphA and EphB class receptors, the largest group of receptor tyrosine kinases, and their membrane bound ephrin ligands mediate cell-to-cell contact signaling involved in numerous cell functions including cell migration, proliferation, survival, axon guidance, synaptogenesis, and vascular remodeling among other roles 35 – 38 .…”

Section: Introductionmentioning

confidence: 76%

“…Previous findings suggest that vascular distribution and activation of ephrin type-A receptor 4 (EphA4) influences hippocampal neurogenesis 30 , 31 . Given its emerging significance in vascular function 32 – 34 , we sought to determine the role of EphA4 in rmTBI-mediated effects using endothelial cell (EC)-specific EphA4 knockout (KO) mice (EphA4f. /f /Tie2-Cre) and wild type (WT) mice (EphA4f.…”

Section: Resultsmentioning

confidence: 99%

“…/f and male EphA4f. /f /Tie2-Cre +/− on the CD1 background were bred as previously described 32 , 33 to generate the appropriate number of male mice, reared until age P60–P90, required for each experiment. All experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were conducted performed under the approval of the Virginia Tech Institutional Animal Care and Use Committee (IACUC; #17-093) and the Virginia-Maryland Regional College of Veterinary Medicine.…”

Section: Methodsmentioning

confidence: 99%

“…Brains were harvested at both 9 and 24 days post-primary injury (dppi) and immediately fresh frozen and embedded in OCT. Serial coronal sections were processed on a cryostat (Cryostar, Fisher Scientific) using five 30 μm coronal sections spaced ten sections apart and placed in the − 80 °C freezer as previously performed 32 , 41 – 43 . Sections were fixed with 10% buffered formalin (Fisher Scientific) then washed with 1X phosphate-buffered saline (PBS) and blocked for 1 h in 2% fish gelatin/0.2%Triton.…”

Section: Methodsmentioning

confidence: 99%

“…/f /Tie2-Cre) and wild type (WT) mice (EphA4f. /f ) 32 , 33 , the current study sought to advance our understanding of Eph signaling in aberrant neurogenesis as it relates to brain trauma. Our findings uncovered the direct involvement of atypical neurogenesis in the observed hippocampal-dependent learning and memory impairments following rmTBI.…”

Section: Introductionmentioning

confidence: 99%

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Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments

Greer

Basso

Kelly

et al. 2020

Sci Rep

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Brain injury resulting from repeated mild traumatic insult is associated with cognitive dysfunction and other chronic co-morbidities. The current study tested the effects of aberrant neurogenesis in a mouse model of repeated mild traumatic brain injury (rmTBI). Using Barnes Maze analysis, we found a significant reduction in spatial learning and memory at 24 days post-rmTBI compared to repeated sham (rSham) injury. Cell fate analysis showed a greater number of BrdU-labeled cells which co-expressed Prox-1 in the DG of rmTBI-injured mice which coincided with enhanced cFos expression for neuronal activity. We then selectively ablated dividing neural progenitor cells using a 7-day continuous infusion of Ara-C prior to rSham or rmTBI. This resulted in attenuation of cFos and BrdU-labeled cell changes and prevented associated learning and memory deficits. We further showed this phenotype was ameliorated in EphA4f./f/Tie2-Cre knockout compared to EphA4f./f wild type mice, which coincided with altered mRNA transcript levels of MCP-1, Cx43 and TGFβ. These findings demonstrate that cognitive decline is associated with an increased presence of immature neurons and gene expression changes in the DG following rmTBI. Our data also suggests that vascular EphA4-mediated neurogenic remodeling adversely affects learning and memory behavior in response to repeated insult.

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Section: Introductionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments

Greer

Basso

Kelly

et al. 2020

Sci Rep

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Leptomeningeal anastomoses: Mechanisms of pial collateral remodeling in ischemic stroke

Kaloss

Theus

2022

WIREs Mechanisms of Disease

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Arterial collateralization, as determined by leptomeningeal anastomoses or pial collateral vessels, is a well‐established vital player in cerebral blood flow restoration and neurological recovery from ischemic stroke. A secondary network of cerebral collateral circulation apart from the Circle of Willis, exist as remnants of arteriole development that connect the distal arteries in the pia mater. Recent interest lies in understanding the cellular and molecular adaptations that control the growth and remodeling, or arteriogenesis, of these pre‐existing collateral vessels. New findings from both animal models and human studies of ischemic stroke suggest a multi‐factorial and complex, temporospatial interplay of endothelium, immune and vessel‐associated cell interactions may work in concert to facilitate or thwart arteriogenesis. These valuable reports may provide critical insight into potential predictors of the pial collateral response in patients with large vessel occlusion and may aid in therapeutics to enhance collateral function and improve recovery from stroke. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology

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Collateral Supply in Preclinical Cerebral Stroke Models

Bonnin

Kubis

Charriaut‐Marlangue

2021

Transl. Stroke Res.

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Enhancing the collateral blood supply during the acute phase of cerebral ischemia may limit both the extension of the core infarct, by rescuing the penumbra area, and the degree of disability. Many imaging techniques have been applied to rodents in preclinical studies, to evaluate the magnitude of collateral blood flow and the time course of responses during the early phase of ischemic stroke. The collateral supply follows several different routes at the base of the brain (the circle of Willis) and its surface (leptomeningeal or pial arteries), corresponding to the proximal and distal collateral pathways, respectively. In this review, we describe and illustrate the cerebral collateral systems and their modifications following pre-Willis or post-Willis occlusion in rodents. We also review the potential pharmaceutical agents for stimulating the collateral blood supply tested to date. The time taken to establish a collateral blood flow supply through the leptomeningeal anastomoses differs between young and adult animals and between different species and genetic backgrounds. Caution is required when transposing preclinical findings to humans, and clinical trials must be performed to check the added value of pharmacological agents for stimulating the collateral blood supply at appropriate time points. However, collateral recruitment appears to be a rapid, beneficial, endogenous mechanism that can be stimulated shortly after artery occlusion. It should be considered a treatment target for use in addition to recanalization strategies.

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EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke

Cited by 33 publications

References 62 publications

Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments

Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments

Leptomeningeal anastomoses: Mechanisms of pial collateral remodeling in ischemic stroke

Collateral Supply in Preclinical Cerebral Stroke Models

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