Browsing by Subject "Vascular endothelium"

Now showing 1 - 3 of 3
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    Endothelial Activation, Acute Kidney Injury, and Cognitive Impairment in Pediatric Severe Malaria
    (Wolters Kluwer, 2020-09) Ouma, Benson J.; Ssenkusu, John M.; Shabani, Estela; Datta, Dibyadyuti; Opoka, Robert O.; Idro, Richard; Bangirana, Paul; Park, Gregory; Joloba, Moses L.; Kain, Kevin C.; John, Chandy C.; Conroy, Andrea L.; Pediatrics, School of Medicine
    Objectives: Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors. Design: Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children. Setting: Mulago National Referral Hospital in Kampala, Uganda. Subjects: Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months. Interventions: None. Measurements and main results: Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log10 increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β -0.42, 95% CI, -0.69 to -0.15, p = 0.002; children ≥ 5, β -0.39, 95% CI, -0.67 to -0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau). Conclusions: These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.
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    The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition
    (Cell Press, 2021) Azzoni, Emanuele; Frontera, Vincent; Anselmi, Giorgio; Rode, Christina; James, Chela; Deltcheva, Elitza M.; Demian, Atanasiu S.; Brown, John; Barone, Cristiana; Patelli, Arianna; Harman, Joe R.; Nicholls, Matthew; Conway, Simon J.; Morrissey, Edward; Jacobsen, Sten Eirik W.; Sparrow, Duncan B.; Harris, Adrian L.; Enver, Tariq; de Bruijn, Marella F.T.R.; Pediatrics, School of Medicine
    Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1-/- mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1-/- cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.
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    THE ROLE OF DAP-KINASE IN MODULATING VASCULAR ENDOTHELIAL CELL FUNCTION UNDER FLUID SHEAR STRESS
    (2010-05-05T15:00:50Z) Rennier, Keith; Ji, Julie Ying Hui; Yokota, Hiroki, 1955-; Li, Jiliang
    Atherosclerosis preferentially develops in vascular regions of low or disturbed flow and high spatial gradients. Endothelial cells that line the vessel walls actively participate in translating mechanical stimuli, shear stress due to fluid flow, into intracellular signals to regulate cellular activities. Atherosclerosis is a chronic disease. During its development, a cascade of inflammatory signals alters the arterial endothelial homeostatic functions. Death-associated protein (DAP) kinase and its correlated pathway have been associated with cell apoptosis, turnover, and cytoskeleton remodeling in cellular networks, ultimately leading to changes in cell motility and vascular wall permeability. DAP-kinase is also highly regulated by inflammatory triggers such as TNF-α. This thesis investigates DAP-kinase modulation due to shear stress, and the role of DAP-kinase activity in endothelial responses toward applied shear stress. Using bovine aortic endothelial cells (BAEC), DAP-kinase expression is demonstrated in both sheared (10 dynes/cm2) and static conditions. Overall DAPK expression increased with extended shearing, while the presence of phosphorylated DAPK decreased with applied shear stress, as demonstrated in Western blot analysis. In correlation, DAPK RNA expression profiles were explored to understand pre-translational behavior and to understand just how shear stress influences DAPK expression over time. There is a temporal increase in DAPK mRNA, occurring at earlier time points when compared to DAPK protein expression, displaying the precedence of mRNA expression leading to increased translation into protein. From our apoptosis assay results, shear stress reduces apoptotic and late stage/necrotic cell fractions. The exposure of shear stress potentially plays a role in inhibiting apoptosis activation and TNF-α induced death cascade. Overall, the apoptosis activity influenced by shear further exhibits a possible connection between shear stress and apoptosis inhibition. The shear stress ultimately decreases overall apoptosis, while DAPK expression is increased. Therefore, DAPK may have a function in other possible mechano-transduction cascades, when endothelial cells are exposed to constant shear. Our data suggests shear stress modulation of DAP-kinase expression and activity, and the potential crosstalk of mechano-transduction and DAPK/apoptosis pathway, may lead to further understanding the responsibility of DAPK in endothelial cell function.