Dataset Information

Brain Endothelial Cells Activate Neuroinflammatory Pathways in Response to Early Cerebral Small Vessel Disease (CSVD) Patients' Plasma.

ABSTRACT: The pathogenesis of cerebral small vessel disease (CSVD) is largely unknown. Endothelial disfunction has been suggested as the turning point in CSVD development. In this study, we tested the effect of plasma from CSVD patients on human cerebral microvascular endothelial cells with the aim of describing the pattern of endothelial activation. Plasma samples from three groups of young subjects have been tested: PTs (subjects affected by early stage CSVD); CTRLs (control subjects without abnormalities at MRI scanning); BDs (blood donors). Human Brain Endothelial Cells 5i (HBEC5i) were treated with plasma and total RNA was extracted. RNAs were pooled to reduce gene expression-based variability and NGS analysis was performed. Differentially expressed genes were highlighted comparing PTs, CTRLs and BDs with HBEC5i untreated cells. No significantly altered pathway was evaluated in BD-related treatment. Regulation of p38 MAPK cascade (GO:1900744) was the only pathway altered in CTRL-related treatment. Indeed, 36 different biological processes turned out to be deregulated after PT treatment of HBEC5i, i.e., the cytokine-mediated signaling pathway (GO:0019221). Endothelial cells activate inflammatory pathways in response to stimuli from CSVD patients' plasma, suggesting the pathogenetic role of neuroinflammation from the early asymptomatic phases of cerebrovascular disease.

SUBMITTER: Cifu A

PROVIDER: S-EPMC10669613 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Brain Endothelial Cells Activate Neuroinflammatory Pathways in Response to Early Cerebral Small Vessel Disease (CSVD) Patients' Plasma.

Cifù Adriana A Janes Francesco F Mio Catia C Domenis Rossana R Pessa Maria Elena ME Garbo Riccardo R Curcio Francesco F Valente Mariarosaria M Fabris Martina M

Biomedicines 20231114 11

The pathogenesis of cerebral small vessel disease (CSVD) is largely unknown. Endothelial disfunction has been suggested as the turning point in CSVD development. In this study, we tested the effect of plasma from CSVD patients on human cerebral microvascular endothelial cells with the aim of describing the pattern of endothelial activation. Plasma samples from three groups of young subjects have been tested: PTs (subjects affected by early stage CSVD); CTRLs (control subjects without abnormaliti ...[more]

PMID: 38002055

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Project description:BackgroundThe cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH.MethodsWe prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline.ResultsWe recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model.ConclusionPlasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population.

Project description:Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying pathogenesis is poorly understood, but both neuroinflammation and increased blood-brain barrier permeability have been hypothesized to play a role, and preclinical studies suggest the two processes may be linked. We used PET magnetic resonance to simultaneously measure microglial activation using the translocator protein radioligand 11C-PK11195, and blood-brain barrier permeability using dynamic contrast enhanced MRI. A case control design was used with two disease groups with sporadic SVD (n = 20), monogenic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL), and normal controls (n = 20) were studied. Hotspots of increased glial activation and blood-brain barrier permeability were identified as values greater than the 95th percentile of the distribution in controls. In sporadic SVD there was an increase in the volume of hotspots of both 11C-PK11195 binding (P = 0.003) and blood-brain barrier permeability (P = 0.007) in the normal appearing white matter, in addition to increased mean blood-brain barrier permeability (P < 0.001). In CADASIL no increase in blood-brain barrier permeability was detected; there was a non-significant trend to increased 11C-PK11195 binding (P = 0.073). Hotspots of 11C-PK11195 binding and blood-brain barrier permeability were not spatially related. A panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured in each participant; principal component analysis was performed and the first component related to blood-brain barrier permeability and microglial activation. Within the sporadic SVD group both hotspot and mean volume blood-brain barrier permeability values in the normal appearing white matter were associated with dimension 1 (β = 0.829, P = 0.017, and β = 0.976, P = 0.003, respectively). There was no association with 11C-PK11195 binding. No associations with blood markers were found in the CADASIL group. In conclusion, in sporadic SVD both microglial activation and increased blood-brain barrier permeability occur, but these are spatially distinct processes. No evidence of increased blood-brain barrier permeability was found in CADASIL.

Dataset Information

Brain Endothelial Cells Activate Neuroinflammatory Pathways in Response to Early Cerebral Small Vessel Disease (CSVD) Patients' Plasma.

Publications

Brain Endothelial Cells Activate Neuroinflammatory Pathways in Response to Early Cerebral Small Vessel Disease (CSVD) Patients' Plasma.

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