Cerebral Endothelium Research Articles

From Low-Grade Inflammation in Osteoarthritis to Neuropsychiatric Sequelae: A Narrative Review.

Nowadays, osteoarthritis (OA), a common, multifactorial musculoskeletal disease, is considered to have a low-grade inflammatory pathogenetic component. Lately, neuropsychiatric sequelae of the disease have gained recognition. However, a link between the peripheral inflammatory process of OA and the development of neuropsychiatric pathology is not completely understood. In this review, we provide a narrative that explores the development of neuropsychiatric disease in the presence of chronic peripheral low-grade inflammation with a focus on its signaling to the brain. We describe the development of a pro-inflammatory environment in the OA-affected joint. We discuss inflammation-signaling pathways that link the affected joint to the central nervous system, mainly using primary sensory afferents and blood circulation via circumventricular organs and cerebral endothelium. The review describes molecular and cellular changes in the brain, recognized in the presence of chronic peripheral inflammation. In addition, changes in the volume of gray matter and alterations of connectivity important for the assessment of the efficacy of treatment in OA are discussed in the given review. Finally, the narrative considers the importance of the use of neuropsychiatric diagnostic tools for a disease with an inflammatory component in the clinical setting.

IL-17/CXCL5 signaling within the oligovascular niche mediates human and mouse white matter injury.

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling that acts on the cerebral endothelia through IL-17Rb to increase both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of OPCs with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduced vessel-associated OPCs by reducing endothelial CXCL5 expression. In multiple human cohorts, blood levels of CXCL5 function as a diagnostic and prognostic biomarker of vascular cognitive impairment.

Global-Scale Profiling of Differential Expressed Lysine-Lactylated Proteins in the Cerebral Endothelium of Cerebral Ischemia-Reperfusion Injury Rats.

Acute ischemic stroke (AIS) is a serious threat to human health. Following AIS, cerebral ischemia-reperfusion injury (CIRI) must be treated to improve prognosis. By combining 4D label-free quantitative proteomics with lactylation modification-specific proteomics analysis, we assessed lysine lactylation (Kla) in cortical proteins of a CIRI rat model. We identified a total of 1003 lactylation sites on 469 proteins in this study, gathering quantitative information (PXD034232) on 660 of 310 proteins, which were further classified by cell composition, molecular function, and biological processes. In addition, we analyzed the metabolic pathways, domains, and protein-protein interaction networks. Lastly, we evaluated differentially expressed lysine lactylation sites, determining 49 upregulated proteins and 99 downregulated proteins with 54 upregulated sites and 54 downregulated sites in the experimental group in comparison with the healthy control group. Moreover, we identified the Kla of Scl25a4 and Slc25a5 in the Ca2+ signaling pathway, but the Kla of Vdac1 was eliminated, as confirmed in vivo. Overall, these results provide new insights into lactylation involved in the underlying mechanism of CIRI because this post-translational modification affects the mitochondrial apoptosis pathway and mediates neuronal death. Therefore, this study may enable us to develop new molecules with therapeutic properties, which have both theoretical significance and broad clinical application prospects. A new model of cerebral ischemia-reperfusion injury (CIRI) induced by lactylation through the regulation of key proteins of the Ca2+ signaling pathway.

Endothelial Cells and the Cerebral Circulation.

Endothelial cells form the innermost layer of all blood vessels and are the only vascular component that remains throughout all vascular segments. The cerebral vasculature has several unique properties not found in the peripheral circulation; this requires that the cerebral endothelium be considered as a unique entity. Cerebral endothelial cells perform several functions vital for brain health. The cerebral vasculature is responsible for protecting the brain from external threats carried in the blood. The endothelial cells are central to this requirement as they form the basis of the blood-brain barrier. The endothelium also regulates fibrinolysis, thrombosis, platelet activation, vascular permeability, metabolism, catabolism, inflammation, and white cell trafficking. Endothelial cells regulate the changes in vascular structure caused by angiogenesis and artery remodeling. Further, the endothelium contributes to vascular tone, allowing proper perfusion of the brain which has high energy demands and no energy stores. In this article, we discuss the basic anatomy and physiology of the cerebral endothelium. Where appropriate, we discuss the detrimental effects of high blood pressure on the cerebral endothelium and the contribution of cerebrovascular disease endothelial dysfunction and dementia. © 2022 American Physiological Society. Compr Physiol 12:3449-3508, 2022.

Abstracts from The 39th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical Care

Abstracts from The 39^th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical Care

The Cold Receptor TRPM8 Mediates the Antioxidant and Cytoprotective Effects of Mild Hypothermia in Cerebral Endothelial Cells During Inflammation

Cerebral vascular endothelium, the key component of the neurovascular unit, is most vulnerable to oxidative stress injury. Our previous reports in newborn pigs indicated that brain hypothermia prevents cerebral endothelial injury by oxidative stress caused by neonatal seizures and asphyxia. We used primary cerebral vascular endothelial cells (CVEC) from newborn pigs as an in vitro model of oxidative stress condition in the brain caused by inflammation. During normothermia (37˚C), CVEC respond to a pro‐inflammatory cytokine TNF‐alpha (30 ng/ml) by excessive formation of reactive oxygen species (ROS) leading to cell death by apoptosis (caspase‐3 activation, DNA fragmentation, loss of cell‐cell contacts). Remarkably, mild hypothermia (24.5°C) reduced ROS and prevented apoptosis in CVEC exposed to TNF‐alpha. We tested the hypothesis that the cold sensing menthol receptor TRPM8 mediates the cytoprotective effects of mild hypothermia in cerebral endothelium. TRPM8 (mRNA and protein) is expressed in CVEC. The TRPM8 agonist icilin (5 µM) reduced ROS and prevented apoptosis in CVEC exposed to TNF‐alpha at 37˚C, thus mimicking the cytoprotective effects of mild cooling. The TRPM8 antagonist AMTB (20 µM) reversed the icilin‐mediated cytoprotective effects during inflammation. The cell surface biotinylation technique suggested that mild hypothermia and icilin (at 37˚C) promote a time‐dependent TRPM8 translocation from an intracellular compartment to the plasma membrane concomitantly with the receptor activation. We used the in vitro model of the blood‐brain barrier (BBB) to test the functional consequences of TRPM8‐mediated cytoprotection. Confluent monolayers of CVEC cultured on transwell inserts with semipermeable membranes were exposed to TNF‐alpha during normothermia and mild hypothermia conditions. The BBB properties were detected by transendothelial electrical resistance (TEER) and the permeability to 3 kDa fluorescent Dextran. During a 2‐6 h exposure to TNF‐alpha at 37°C, TEER was time‐dependently reduced, and the Dextran permeability was elevated indicating the BBB opening. Mild hypothermia (24.5°C) and icilin (at 37˚C) largely preserved the BBB properties during inflammatory conditions. Overall, our findings demonstrate that mild hypothermia, via a TRPM8‐mediated mechanism, reduces oxidative stress, promotes cell survival, and prevents BBB damage during inflammation. The TRPM8 targeting approaches may provide a promising therapeutic strategy for cerebrovascular disease caused by brain inflammation.

Effect of Hypercapnia and Hypoxia on the Physiology and Metabolism of the Cerebral Endothelium under Ischemic Conditions

Effect of Hypercapnia and Hypoxia on the Physiology and Metabolism of the Cerebral Endothelium under Ischemic Conditions

H-2Kb and H-2Db class I molecules on cerebral endothelium differentially modulate CD8 T cells dynamics and pathological outcomes in experimental cerebral malaria

Abstract Immune mechanisms of neuropathology in human cerebral malaria are not fully understood. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we sought to define the contribution of cerebral endothelial cell (CEC) MHC class I antigen presentation, to the pathogenesis and lethality of ECM. CD8 T cell interactions with class I molecules on CECs has been put forward as a putative mechanism for ECM. However, the importance of this interaction has not been confirmed molecularly in vivo. We therefore hypothesized that conditional ablation of antigen presentation by H-2Kb and H-2Db class I molecules specifically on brain endothelium would result in controlled modulation of activation and entry of parasite-specific CD8 T cells, attenuating pathology. To test this, we crossed endothelium-specific CDH5-Cre mice with our novel H-2Kb and H-2Db LoxP mice to create endothelium-specific cKO of either or both class I molecules. 2-photon imaging revealed that each discreet class I molecule influenced differential T cell dynamics at the neurovasculature during lethal stage of disease. Furthermore, CD8 T cell activation and infiltration of the brain was distinctly altered, per class I interaction, and vascular permeability at the blood-brain barrier was attenuated, resulting in improved survival of H-2Kb and H-2Db endothelial cKO mice. Together these data demonstrate that parasite-specific CD8 T cells undergo Ag-dependent engagement with H-2Kb or H-2Db class I molecules on CECs in order to coordinate activation, entry, and induction of neuropathology. These studies indicate that modulation of CEC class I restricted antigen presentation may hold therapeutic benefit in cases of severe malaria. Supported by Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship F31 1F31NS116924-01. NIH R01 5R01NS103212-05.

COVID-19: Cellular and Molecular Mechanisms of Brain Damage

The most common clinical manifestation of COVID-19 is bilateral pneumonia, a diffuse, alveolar injury with severe microangiopathy. Systemic infection is accompanied by an increase in circulating chemokines and interleukins in the blood, which penetrate the blood–brain barrier (BBB) and enter the brain. Clinical materials indicate lesions of the brain and peripheral nervous system, as well as neurodegenerative and mental disorders. Due to violations of the cerebral endothelium system and changes in the balance of ACE2-coupled cytochemical processes, coagulopathy develops, leading to microthrombosis and vascular occlusion. The concept of SARS-CoV-2 “neurotropism” is discussed as a rationale for the penetration by the virus into the brain. Infection can occur as axonal transport through the bulbar zone and the olfactory area of the cerebral cortex. Even more common is the “hematogenous pathway” of viral transfection, which includes damage to the vascular endothelium and a violation of the protective role of the BBB. Another concept that explains the mechanism of brain damage relates to the phenomenon of neuroinflammation. Astrocytes and microglia are considered potential targets of the SARS-CoV-2 coronavirus. The dissonance of the biochemical processes of the axis ACE2/ACE and changes in the functions of angiotensin peptides leads to the activation of astroglia with the development of neurodestructive processes in COVID-19.

J147 Reduces tPA-Induced Brain Hemorrhage in Acute Experimental Stroke in Rats.

Background and purposeJ147, a novel neurotrophic compound, was originally developed to treat aging-associated neurological diseases. Based on the broad spectrum of cytoprotective effects exhibited by this compound, we investigated whether J147 has cerebroprotection for acute ischemic stroke and whether it can enhance the effectiveness of thrombolytic therapy with tissue plasminogen activator (tPA).MethodsRats were subjected to transient occlusion of the middle cerebral artery (tMCAO) by insertion of an intraluminal suture or embolic middle cerebral artery occlusion (eMCAO), and treated intravenously with J147 alone or in combination with tPA.ResultsWe found that J147 treatment significantly reduced infarct volume when administered at 2 h after stroke onset in the tMCAO model, but had no effect in eMCAO without tPA. However, combination treatment with J147 plus tPA at 4 h after stroke onset significantly reduced infarct volume and neurological deficits at 72 h after stroke compared with saline or tPA alone groups in the eMCAO model. Importantly, the combination treatment significantly reduced delayed tPA-associated brain hemorrhage and secondary microvascular thrombosis. These protective effects were associated with J147-mediated inhibition of matrix metalloproteinase-9 (MMP9), 15-lipoxygenase-1, and plasminogen activator inhibitor (PAI) expression in the ischemic hemispheres (predominantly in ischemic cerebral endothelium). Moreover, the combination treatment significantly reduced circulating platelet activation and platelet-leukocyte aggregation compared with saline or tPA alone groups at 24 h after stroke, which might also contribute to reduced microvascular thrombosis and neuroinflammation (as demonstrated by reduced neutrophil brain infiltration and microglial activation).ConclusionOur results demonstrate that J147 treatment alone exerts cerebral cytoprotective effects in a suture model of acute ischemic stroke, while in an embolic stroke model co-administration of J147 with tPA reduces delayed tPA-induced intracerebral hemorrhage and confers cerebroprotection. These findings suggest that J147-tPA combination therapy could be a promising approach to improving the treatment of ischemic stroke.

Abstract TP11: G-quadruplexes Regulate The Senescence Factor Cysteine-rich Angiogenic Inducer-61 In Primary Cerebral Endothelial Cells

Senescence in the cerebral endothelium has been proposed as a mechanism that can drive dysfunction of the cerebral vasculature, which precedes vascular dementia. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) is a matricellular protein secreted by cerebral endothelial cells (CEC). CCN1 induces senescence in fibroblasts. Whether CCN1 contributes to senescence of CEC and how it is regulated require further study. Aging has been associated with the formation of four-stranded Guanine-quadruplexes (G4s) in G-rich motifs of DNA and RNA. G4 stabilization regulates transcription and translation either by upregulation or downregulation depending on the gene target. Previously, we showed that aged mice treated with a G4-stabilizing compound had enhanced senescence-associated (SA) phenotypes in their brains, and exhibited cognitive deficits. The expression of human CCN1 can be upregulated via the stabilization of G4s. A sequence in the 3’- untranslated region (UTR) of the CCN1 mRNA has the ability to fold in to G4 in vitro . Thus, we hypothesize that CCN1 is upregulated with aging and induces senescence, and that G4 stabilization upregulates CCN1 in cultured primary CEC. We used whole brain lysates, cerebral vessel fractions, and cultured primary CEC from young (4-months old, mo) and aged (18-mo) female mice to determine the CCN1 levels. SA phenotypes were determined by high-resolution fluorescence microscopy in cultured primary CEC, and we used Thioflavin T to recognize RNA G4s for fluorescence spectra. We found that CCN1 levels were increased in the brains of aging mice (p=0.0314, n=5), in cerebral vessel fractions (p=0.001, n=5), and in cultured primary CEC derived from aged mice (p=0.012, n=3), compared with those derived from young mice. In cultured CEC, a recombinant CCN1 protein induced SA phenotypes, such as SA beta-galactosidase activity (p=0.003, n=3), and double-strand DNA damage (p=0.016, n=3). Furthermore, CCN1 levels were upregulated by a G4 ligand (p=0.0103, n=3), and a G-rich motif in the 3’-UTR of the Ccn1 mRNA folded into a G4 (p=0.008, n=4). In conclusion , we demonstrate that CCN1 induces senescence in cultured primary CEC, and we propose G4 stabilization as a novel mechanism that regulates the SASP component CCN1.

Naringin Attenuates Leukocyte Adhesion to Cerebral Endothelium in Type 2 Diabetic Rats

Background: The increased accumulation of advanced glycation end products (AGEs) under diabetes conditions can promote oxidative stress and inflammation in vasculature and contribute to endothelial dysfunction. Naringin, a flavonoid compound that occurs naturally in citrus fruits, has been shown to have anti-diabetic and anti-oxidant properties. Objective: To investigate the efficacy of naringin in the improvement of diabetes-induced leukocyte adhesion to cerebral endothelium through AGEs-RAGE-NF-κB pathway. Materials and Methods: Six-week-old Sprague-Dawley were divided into three groups; normal group (CON: n=8), type 2 diabetes group (DM2: n=8), and type 2 diabetes group with naringin supplementation (DM2-NG: n=8). Rats were fed with high-fat diet for four weeks, followed by a single STZ injection to induce type 2 diabetes. Naringin was supplemented daily by oral gavage feeding (50 mg/kg BW). Twelve weeks after STZ injection with or without naringin supplementation, fasting blood glucose (FBG), serum insulin and calculated homeostatic model assessment of insulin resistance (HOMA-IR) were examined. Leukocyte adhesion at postcapillary venule was carried out by using intravital fluorescence microscopy. AGEs, RAGE and TNF-α were detected by ELISA whereas NF-κB, ICAM-1 were investigated using Western blot analysis and MDA was determined by TBARs assay. Results: After 12 weeks of naringin feeding into DM2-NG rats, the FBG levels decreased 62.8% compared to those without supplementation. Moreover, the β-cell function was improved by reducing serum insulin levels and HOMA-IR. Not only the endothelial function was improved by reducing the number of leukocyte adhesion, but the expression of ICAM-1 was also decreased. Naringin supplementation also attenuated inflammation and oxidative stress by reducing the levels of AGEs, RAGE, and its downstream molecules, NF-κB-TNF-α. Conclusion: It is suggested that supplementation with naringin in type 2 diabetes rat model can reduce leukocyte adhesion to vascular endothelium via anti-hyperglycemic, anti-oxidant and anti-inflammatory effects through AGEs-RAGE-NF-κB-TNF-α-ICAM-1 signaling pathway. Keywords: Type 2 diabetic rats; Naringin; Leukocyte adhesion; Endothelial dysfunction

G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells.

Senescence in the cerebral endothelium has been proposed as a mechanism that can drive dysfunction of the cerebral vasculature, which precedes vascular dementia. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) is a matricellular protein secreted by cerebral endothelial cells (CEC). CCN1 induces senescence in fibroblasts. However, whether CCN1 contributes to senescence in CEC and how this is regulated requires further study. Aging has been associated with the formation of four-stranded Guanine-quadruplexes (G4s) in G-rich motifs of DNA and RNA. Stabilization of the G4 structures regulates transcription and translation either by upregulation or downregulation depending on the gene target. Previously, we showed that aged mice treated with a G4-stabilizing compound had enhanced senescence-associated (SA) phenotypes in their brains, and these mice exhibited enhanced cognitive deficits. A sequence in the 3′-UTR of the human CCN1 mRNA has the ability to fold into G4s in vitro. We hypothesize that G4 stabilization regulates CCN1 in cultured primary CEC and induces endothelial senescence. We used cerebral microvessel fractions and cultured primary CEC from young (4-months old, m/o) and aged (18-m/o) mice to determine CCN1 levels. SA phenotypes were determined by high-resolution fluorescence microscopy in cultured primary CEC, and we used Thioflavin T to recognize RNA-G4s for fluorescence spectra. We found that cultured CEC from aged mice exhibited enhanced levels of SA phenotypes, and higher levels of CCN1 and G4 stabilization. In cultured CEC, CCN1 induced SA phenotypes, such as SA β-galactosidase activity, and double-strand DNA damage. Furthermore, CCN1 levels were upregulated by a G4 ligand, and a G-rich motif in the 3′-UTR of the Ccn1 mRNA was folded into a G4. In conclusion, we demonstrate that CCN1 can induce senescence in cultured primary CEC, and we provide evidence that G4 stabilization is a novel mechanism regulating the SASP component CCN1.

Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function.

Variants in the ring finger protein 213 (RNF213) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease. To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology. In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines. Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.

361. Aseptic Meningitis Associated to SARS Cov2 Infection and MIS-C: Pediatric Presentation of Covid-19

BackgroundNovel SARS CoV2 may target the central nervous system and several neurological symptoms have been reported in patients with Coronavirus disease (COVID-19). Mucocutaneous and inflammatory symptoms are important in pediatric population associated to immune dysregulation. There are few reports of clinical manifestations in children and less frequently the isolation and affection of Central Nervous System.MethodsA previously healthy four months female infant with familiar contact to SARS-CoV2 four weeks ago. Start with fever of 104°F, vomiting, maculopapular rash on the anterior thorax and upper extremities involving the palms and soles associated with edema. On physical examination, irritable, bulging anterior fontanelle, non-purulent bilateral conjunctival injection, cheilitis and rash was confirmed. ResultsLaboratory findings: thrombocytopenia, elevated D-Dimer, fibrinogen, PCT, CRP, ferritin and ESR with hypoalbuminemia. MIS-C is integrated with cutaneous, gastrointestinal and neurological affections. Empirically ceftriaxone, vancomycin and acyclovir are started due to suspicion of meningoencephalitis. RT-PCR for SARS-CoV-2 positive. CSF: transparent appearance, slightly xanthochromic color, coagulation and negative film. Proteins 105 mg / dl, glucose 45 mg / dl, leukocytes 121 mm3, erythrocytes 66 mm3, PMN 8% and MNN 92%. Negative culture,PCR Herpes Virus negative,Viral load for SARS CoV2 in CSF 3,400 cop / ml and plasma 118,900 cop / ml, Aseptic meningitis is confirmed by SARS-CoV-2. Antiviral and antibiotics are discontinued and Gamma globulin and methylprednisolone are administered. Evolving favorably and egress at 6th day to complete oral steroid treatment for 3 more day.ConclusionThe mechanism by which SARS-CoV2 affects the CNS is still unknown.This findings suggests direct infection can be possible. Although it is also described vascular affection has been found that the Spike protein of the virus binds to ACE-2 receptor present in the cerebral vascular endothelium. Neurological manifestations have been described even without respiratory symptoms. A novel pediatric case with viral load for SARS-CoV-2 in CSF is demonstrated. Importance of detecting SARS-CoV-2 in children with encephalitis, which can progress satisfactorily.Disclosures All Authors: No reported disclosures

MALAT1 improves functional recovery after traumatic brain injury through promoting angiogenesis in experimental mice

As a highly evolutionary conserved lncRNA, MALAT1 was first demonstrated to associate with metastasis of lung tumor by promoting angiogenesis. Activated vasculature was recently indicated to assist neurogenesis by secreting neurotrophic factor Ang1 (Angiopoietin-1). The purpose of this study is to investigate the potential role of MALAT1 in angiogenesis following traumatic brain injury (TBI). Adult male mice were subjected to controlled cortical impact (CCI) and brain microvascular endothelial cells were exposed to oxygen-glucose deprivation (OGD). MALAT1 RNA levels were quantified by qRT-PCR in different cells of CNS and located by RNA-FISH. Angiogenesis were measured by cell viability, migration assay, tube formation assay in vitro, and immunohistochemistry in vivo. Expression of Angiopoietin-1 was assessed by Western blot. Neurological functions were performed by NSS, Wire grip and MWM tests. Our results indicated that 1) MALAT1 RNA was localized in cerebral endothelium, enhanced by OGD stimuli. 2) Inhibition of MALAT1 by siRNA suppressed angiogenesis, as indicated by endothelial viability, tube formation, migration, and functional vessel density. 3) MALAT1 inhibition further decreased Ang1 expression in the endothelium. 4) Mice with MALAT1 inhibition exhibited worse behavioral performances (NSS, wire grip, Morris water maze), as compared to control. MALAT1 could promote angiogenesis, subsequently contributing to the Ang1 synthesis from active vasculature. It may eventually benefit to functional recovery following TBI.

A functional cerebral endothelium is necessary to protect against cognitive decline

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included NemoFl controls and three NemobeKO groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in NemobeKO mice and were not countered by treatments. Cerebrovascular function was compromised in NemobeKO groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. NemobeKO mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.

Features of nervous system damage in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune process that increases the risk of arterial and venous thrombosis. The mechanism of damage to the central nervous system (CNS) can be not only due to thrombosis, but also antiphospholipid antibodies (APA) circulating in the peripheral blood. The latter can damage the cerebral vascular endothelium, alter the resistance of the blood-brain barrier and penetrate into the central nervous system, exerting a damaging effect on astroglia and neurons, as evidenced by the release of neurospecific proteins into the peripheral bloodstream. The role of APS in developing cerebral ischemia, migraine, epilepsy, chorea, transverse myelitis, multiple sclerosis, cognitive impairment and mental disorders, as well as the peripheral nervous system is described. It should also be noted about a role of APS for emerging neurological disorders in COVID-19, enabled apart from thrombogenesis due to APA via 2 potential mechanisms - molecular mimicry and neoepitope formation. Further study of the APS pathogenesis and interdisciplinary interaction are necessary to develop effective methods for patient management.

Chronic cerebral lipocalin 2 exposure elicits hippocampal neuronal dysfunction and cognitive impairment

Lipocalin 2 (LCN2) is a pleiotropic molecule that is induced in the central nervous system (CNS) in several acute and chronic pathologies. The acute induction of LCN2 evolved as a beneficial process, aimed at combating bacterial infection through the sequestration of iron from pathogens, while the role of LCN2 during chronic, non-infectious disease remains unclear, and recent studies suggest that LCN2 is neurotoxic. However, whether LCN2 is sufficient to induce behavioral and cognitive alterations remains unclear. In this paper, we sought to address the role of cerebral LCN2 on cognition in both acute and chronic settings. We demonstrate that LCN2 is robustly induced in the CNS during both acute and chronic inflammatory conditions, including LPS-based sepsis and cancer cachexia. In vivo, LPS challenge results in a global induction of LCN2 in the central nervous system, while cancer cachexia results in a distribution specific to the vasculature. Similar to these in vivo observations, in vitro modeling demonstrated that both glia and cerebral endothelium produce and secrete LCN2 when challenged with LPS, while only cerebral endothelium secrete LCN2 when challenged with cancer-conditioned medium. Chronic, but not short-term, cerebral LCN2 exposure resulted in reduced hippocampal neuron staining intensity, an increase in newborn neurons, microglial activation, and increased CNS immune cell infiltration, while gene set analyses suggested these effects were mediated through melanocortin-4 receptor independent mechanisms. RNA sequencing analyses of primary hippocampal neurons revealed a distinct transcriptome associated with prolonged LCN2 exposure, and ontology analysis was suggestive of altered neurite growth and abnormal spatial learning. Indeed, LCN2-treated hippocampal neurons display blunted neurite processes, and mice exposed to prolonged cerebral LCN2 levels experienced a reduction in spatial reference memory as indicated by Y-maze assessment. These findings implicate LCN2 as a pathologic mediator of cognitive decline in the setting of chronic disease.

Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease.

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.