Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains

Substantial variability exists in collateral density and ischemia-induced collateral growth among species. To begin to probe the underlying mechanisms, which are unknown, we characterized two mouse strains with marked differences in both parameters. Immediately after femoral artery ligation, collateral and foot perfusion were lower in BALB/c than C57BL/6 ( P < 0.05 here and below), suggesting fewer pre-existing collaterals. This was confirmed with angiography and immunohistochemistry (∼35% fewer collaterals in the BALB/c's thigh). Recovery of hindlimb perfusion was attenuated in BALB/c, in association with 54% less collateral remodeling, reduced angiogenesis, greater ischemia, and more impaired hindlimb use. Densities of CD45+ and CD4+ leukocytes around collaterals increased similarly, but TNF-α expression was 50% lower in BALB/c, which may contribute to reduced collateral remodeling. In normal tissues, compared with C57BL/6, BALB/c exhibit an altered arterial branching pattern and, like skeletal muscle above, have 30% fewer collaterals in intestine and, remarkably, almost none in pial circulation, resulting in greatly impaired perfusion after cerebral artery occlusion. Ischemic induction of VEGF-A was attenuated in BALB/c. Analysis of a C57BL/6 × BALB/c recombinant inbred strain dataset identified a quantitative trait locus for VEGF-A mRNA abundance at or near the Vegfa locus that associates with lower expression in BALB/c. This suggests a cis-acting polymorphism in the Vegfa gene in BALB/c could contribute to reduced VEGF-A expression and, in turn, the above deficiencies in this strain. These findings suggest these strains offer a model to investigate genetic determinants of collateral formation and growth in ischemia.

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Abstract T P229: Deletion of Voltage Gated Proton Channel in Microglial Cells is Neurovascular Protective After Ischemic Brain Injury

Stroke ◽

10.1161/str.46.suppl_1.tp229 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Weiguo Li ◽

Becca Ward ◽

Mohammed Abdelsaid ◽

Tianzheng Yu ◽

Yisang Yoon ◽

...

Keyword(s):

Ischemic Stroke ◽

Ischemia Reperfusion ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Proton Channel ◽

Ros Generation ◽

Vascular Integrity ◽

Voltage Gated ◽

Underlying Mechanisms ◽

Cerebral Artery Occlusion

Despite the failure of antioxidant treatments in clinical trials, the undoubted role of reactive oxygen species (ROS) in neurovascular damage after ischemic stroke calls for a more targeted approach. ROS production by microglia, the primary resident immune cells in the brain, is a key event of this process in ischemic stroke. Voltage gated proton channel, Hv1, is localized primarily to microglia and sustains NADPH oxidase activity. Deletion of Hv1 is neuroprotective after permanent middle cerebral artery occlusion (MCAO). We hypothesized that Hv1-mediated microglial ROS generation is also critical for vascular integrity and contributes to reperfusion injury after transient ischemic stroke. The wildtype (WT) and Hv1 knockout (KO) rats (n=4) were subjected to permanent or 3/24 h transient MCAO. The neurological deficiency, infarct, hemorrhagic transformation, and edema ratio were assessed. We found that in both permanent and transient MCAO model, KO rats develop smaller infarct, less vascular injury, edema, and hemorrhagic transformation, resulting in better short-term functional outcome. These results suggest that deletion of microglial Hv1 channel is vasculoprotective after ischemia/reperfusion and the underlying mechanisms need to be further studied.

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Analysis of 19 mouse strains demonstrates that genetic variations in pial collateral dimensions are the major determinants of severity of infarct volume after middle cerebral artery occlusion (MCAO)

Cardiovascular Revascularization Medicine ◽

10.1016/j.carrev.2009.04.099 ◽

2009 ◽

Vol 10 (4) ◽

pp. 273-274

Author(s):

Hua Zhang ◽

Sehoon Keum ◽

Douglas Marchuk ◽

Robert Sealock ◽

James Faber

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Infarct Volume ◽

Artery Occlusion ◽

Genetic Variations ◽

Mouse Strains ◽

Cerebral Artery Occlusion

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Quantitative Trait Loci on Chromosomes 10 and 11 Influencing Mandible Size of SMXA RI Mouse Strains

Journal of Dental Research ◽

10.1177/154405910208100714 ◽

2002 ◽

Vol 81 (7) ◽

pp. 501-504 ◽

Cited By ~ 30

Author(s):

A. Dohmoto ◽

K. Shimizu ◽

Y. Asada ◽

T. Maeda

Keyword(s):

Quantitative Trait Locus ◽

Quantitative Trait ◽

Major Gene ◽

Recombinant Inbred Strain ◽

Mouse Strains ◽

Chromosome 11 ◽

Significant Qtls ◽

Mandible Length ◽

Trait Locus ◽

Mandible Size

Predicting the mandible size before the termination of growth of the maxillofacial bones is essential in pedodontics as well as for the predictions needed for genetic analysis. Here, Quantitative Trait Locus (QTL) analysis was used to detect the chromosomal regions responsible for the mandible length between the menton and gonion in an SMXA recombinant inbred strain of mice. Around the region 60 cM from the centromere in chromosome 10, the logarithm of the odds score showed a higher than suggestive level. Around the regions 13 cM and 16 cM in chromosome 11, two significant QTLs were detected. Analysis of genotypes from loci corresponding to those QTLs revealed a large mandible when the region between the markers Hba and D11Mit163 and D10Mit70 and D10Mit136 indicated the genotype from the A/J and SM/J alleles, respectively. These results suggest that the major gene(s) responsible for mandible length are located in these regions.

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Abstract 150: Protein Nitration Impairs Myogenic Reactivity of Cerebral Vessels in Both Ischemic & Non-ischemic Hemispheres

Stroke ◽

10.1161/str.44.suppl_1.a150 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Maha M Coucha ◽

Weiguo Li ◽

Susan C Fagan ◽

Adviye Ergul

Keyword(s):

Ex Vivo ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Oxidase Inhibitor ◽

Myogenic Tone ◽

Protein Nitration ◽

Cerebrovascular Autoregulation ◽

Male Wistar Rats ◽

Underlying Mechanisms ◽

Cerebral Artery Occlusion

Cerebrovascular autoregulation is critical to maintain constant perfusion during ischemic brain injury. It is known that ischemia/reperfusion (I/R) injury and resulting oxidative stress impair vessel reactivity in ischemic (IS) side. Yet the behavior of vessels in nonischemic (NIS) side is still unexplored. Hypothesis: I/R injury impairs myogenic tone of vessels in both IS & NIS hemispheres via increased peroxynitrite (ONOO - ) generation. Methods: Male Wistar rats (n=8) were subjected to sham or 30 min middle cerebral artery occlusion (MCAO)/45 min reperfusion. Rats were administered saline, ONOO - decomposition catalyst FeTPPs (20 mg/kg) or nitration inhibitor epicatechin (30mg/kg) at reperfusion. In another set of animals, MCA isolated from control rats were exposed to ex-vivo hypoxia with and without gp-91 tat (NADPH oxidase inhibitor 1μM), L-NAME (0.3 mM) and Catalase (1000 u/ml) during reoxygenation. The tone of MCAs across the pressure range was measured using pressurized arteriograph. Nitrotyrosine levels in MCAs from both hemispheres were evaluated using immunoblotting. Results: I/R injury impaired myogenic tone of vessels in both IS & NIS hemispheres albeit to a different degree. Vessels exposed to ex-vivo hypoxia experienced similar loss of myogenic tone. Inhibiting ONOO - by FeTPPs and nitration by epicatechin restored myogenic tone of vessels from both hemispheres back to normal, while inhibiting hydrogen peroxide had no effect. Nitration was significantly increased in both IS (**p<0.01) & NIS hemispheres (*<p0.05) vs sham. Treatment with epicatechin efficiently reduced the extent of nitration back to normal. Conclusion: These results support our hypothesis that I/R injury impairs myogenic tone in BOTH IS and NIS hemispheres and protein nitration due to increased ONOO - production is one of the underlying mechanisms of loss of tone.(† p<0.001, * p< 0.05 vs Sham, # p<0.001 vs IS, *p<0.05,***p<0.001 vs NIS)

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Abstract P735: QPCR Panel Profiling Reveals MiRNAs That Modulate Microglial Activation in Aged Males Isolated After Stroke

Stroke ◽

10.1161/str.52.suppl_1.p735 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Anik Banerjee ◽

Anil Kiran Chokkalla ◽

Julia Shi ◽

Juneyoung Lee ◽

Venugopal Reddy Venna ◽

...

Keyword(s):

Social Isolation ◽

Microglial Activation ◽

Artery Occlusion ◽

Post Stroke ◽

Intracellular Release ◽

Immune Mediated ◽

Microglial Phenotype ◽

Novel Biomarkers ◽

Underlying Mechanisms ◽

Cerebral Artery Occlusion

Introduction: Social isolation (SI) after stroke is associated with increased ischemic injury and significantly delayed recovery due to exacerbation of microglial activation and immune mediated pro-inflammatory mechanisms. Studies have identified miRNAs that modulate and regulate this inflammatory transition through inflammasome NLRP3 activation. However, studies examining miRNA-based microglial activation in SI within the neuro-immune landscape are limited. We investigated miRNA profiles in aged mice to provide biomarkers and to identify underlying mechanisms related to microglial activation within the cerebral environment to mitigate this pathological microglial phenotype. Methods: Aged C57BL/6 male mice (18-20 months) were subjected to a 60-minute middle cerebral artery occlusion (MCAO) followed by reperfusion and were assigned to either (SI) or continued pair-housing (PH) immediately after stroke. On day 15, mice were sacrificed, and plasma samples were subjected to microRNAome (miRNAome) analysis. Top miRNAs were identified using bioinformatics frameworks and pathway analysis was performed using KEGG platform. Flow Cytometry (FACS) was performed on brain tissue and blood to determine if stroke or SI leads to changes in microglial and systemic myeloid activation. Results: The whole miRNAome panel analysis revealed 12 differentially expressed miRNAs (FC of 3 or higher) within the plasma following volcano plot and unsupervised hierarchical clustering analysis confirmed by qPCR validation (P< 0.05). Network analysis revealed miR-495-3p as a pivotal node that targeted the largest subset of immune specific genes (P< 0.05); most notable for the inflammasome NLRP3, a regulator of microglial activation. Significant microglial activation was seen in post-stroke SI mice compared to pair-housed cohorts, identified through MHC-II presentation and the intracellular release of pro-inflammatory cytokines. Conclusion: This study provides an overview of the miRNA changes induced by post-stroke isolation. Additionally, these results suggest that there is potential to use plasma-based miRNAs as a source of novel biomarkers. Further, microglial inflammasome specific pathways appear to be involved in post-stroke social isolation.

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tDCS Accelerates the Rehabilitation of MCAO-Induced Motor Function Deficits via Neurogenesis Modulated by the Notch1 Signaling Pathway

Neurorehabilitation and Neural Repair ◽

10.1177/1545968320925474 ◽

2020 ◽

Vol 34 (7) ◽

pp. 640-651 ◽

Cited By ~ 1

Author(s):

Keying Zhang ◽

Ling Guo ◽

Junping Zhang ◽

Gang Rui ◽

Guangzhou An ◽

...

Keyword(s):

Ischemic Stroke ◽

Motor Function ◽

Artery Occlusion ◽

Sprague Dawley ◽

Damage Area ◽

Notch1 Signaling ◽

Sprague Dawley Rats ◽

Underlying Mechanisms ◽

Notch1 Signaling Pathway ◽

Cerebral Artery Occlusion

Background. Ischemic stroke carries a high mortality rate and is a leading cause of severe neurological disability. However, the efficacy of current therapeutic options remains limited. Objective. We aimed to investigate the treatment efficacy of transcranial direct current stimulation (tDCS) in motor function rehabilitation after ischemic stroke and explore the underlying mechanisms. Methods. Male Sprague-Dawley rats with epicranial electrodes were used to establish pathogenetic model through temporary right middle cerebral artery occlusion (MCAO). Subsequently, animals were randomly divided into 4 groups: MCAO + tDCS/sham tDCS, Control + tDCS/sham tDCS. Animals in the groups with tDCS underwent 10 days of cathodal tDCS totally (500 µA, 15 minutes, once a day). During and after tDCS treatment, the motor functions of the animals, ischemic damage area, proliferation and differentiation of neural stem cells (NSCs), and distribution, and protein expression of Notch1 signaling molecules were detected. Results. The rehabilitation of MCAO-induced motor function deficits was dramatically accelerated by tDCS treatment. NSC proliferation in the subventricular zone (SVZ) was significantly increased after MCAO surgery, and tDCS treatment promoted this process. Additionally, NSCs probably migrated from the SVZ to the ischemic striatum and then differentiated into neurons and oligodendrocytes after MCAO surgery, both of which processes were accelerated by tDCS treatment. Finally, tDCS treatment inhibited the activation of Notch1 signaling in NSCs in the ischemic striatum, which may be involved in NSC differentiation in the MCAO model. Conclusion. Our results suggest that tDCS may exert therapeutic efficacy after ischemic stroke in a regenerative medical perspective.

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Cerebral Organoids Repair Ischemic Stroke Brain Injury

Translational Stroke Research ◽

10.1007/s12975-019-00773-0 ◽

2019 ◽

Vol 11 (5) ◽

pp. 983-1000 ◽

Cited By ~ 2

Author(s):

Shu-Na Wang ◽

Zhi Wang ◽

Tian-Ying Xu ◽

Ming-He Cheng ◽

Wen-Lin Li ◽

...

Keyword(s):

Brain Injury ◽

Infarct Volume ◽

Brain Regions ◽

Artery Occlusion ◽

Stroke Treatment ◽

Cell Based Therapy ◽

Neural Apoptosis ◽

Underlying Mechanisms ◽

Cerebral Artery Occlusion

AbstractStroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.

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