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1.
Elife ; 92020 10 05.
Article in English | MEDLINE | ID: mdl-33016877

ABSTRACT

Cortical neural activity is coupled to local arterial diameter and blood flow. However, which neurons control the dynamics of cerebral arteries is not well understood. We dissected the cellular mechanisms controlling the basal diameter and evoked dilation in cortical arteries in awake, head-fixed mice. Locomotion drove robust arterial dilation, increases in gamma band power in the local field potential (LFP), and increases calcium signals in pyramidal and neuronal nitric oxide synthase (nNOS)-expressing neurons. Chemogenetic or pharmocological modulation of overall neural activity up or down caused corresponding increases or decreases in basal arterial diameter. Modulation of pyramidal neuron activity alone had little effect on basal or evoked arterial dilation, despite pronounced changes in the LFP. Modulation of the activity of nNOS-expressing neurons drove changes in the basal and evoked arterial diameter without corresponding changes in population neural activity.


Subject(s)
Cerebral Arteries/physiopathology , Interneurons/metabolism , Nitric Oxide Synthase Type I/genetics , Somatosensory Cortex/metabolism , Animals , Cerebral Arteries/metabolism , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type I/metabolism
2.
J Transl Med ; 15(1): 55, 2017 03 06.
Article in English | MEDLINE | ID: mdl-28264687

ABSTRACT

OBJECTIVE: Low to moderate inorganic arsenic (iAs) exposure is independently associated with cardiovascular disease (CVD), particularly for patients with diabetes mellitus (DM). The mechanism of increased CVD risk from iAs exposure in DM has not been adequately characterized. We evaluated whether increasing concentrations of glucose enhance the effects of iAs on platelet and megakaryocyte activity, key steps in atherothrombosis. METHODS: Healthy donor whole blood was prepared in a standard fashion and incubated with sodium arsenite in a range from 0 to 10 µM. iAs-induced platelet activation was assessed by platelet receptor CD62P (P-selectin) expression and monocyte-platelet and leukocyte-platelet aggregation (MPA and LPA, respectively) in the presence of increasing sodium arsenite and glucose concentrations. Megakaryocyte (Meg-01) cell adhesion and gene expression was assessed after incubation with or without iAs and increasing concentrations of D-glucose. RESULTS: Platelet activity markers increased significantly with 10 vs. 0 µM iAs (P < 0.05 for all) and with higher D-glucose concentrations. Platelet activity increased significantly following co incubation of 1 and 5 µM iAs concentrations with hyperglycemic D-glucose (P < 0.01 for both) but not after incubation with euglycemic D-glucose. Megakaryocyte adhesion was more pronounced after co incubation with iAs and hyperglycemic than euglycemic D-glucose, while gene expression increased significantly to iAs only after co incubation with hyperglycemic D-glucose. CONCLUSION: We demonstrate that glucose concentrations common in DM potentiate the effect of inorganic arsenic exposure on markers of platelet and megakaryocyte activity. Our results support recent observational cohort data that DM enhances the vasculotoxic effects of arsenic exposure, and suggest that activation of the platelet-megakaryocyte hemostatic axis is a pathway through which inorganic arsenic confers atherothrombotic risk, particularly for patients with DM.


Subject(s)
Arsenic/pharmacology , Blood Platelets/metabolism , Hyperglycemia/pathology , Megakaryocytes/metabolism , Platelet Activation/drug effects , Blood Platelets/drug effects , Blood Platelets/pathology , Cell Adhesion/drug effects , Flow Cytometry , Gene Expression Regulation/drug effects , Humans , Megakaryocytes/drug effects , Megakaryocytes/pathology , NF-kappa B/genetics , NF-kappa B/metabolism , P-Selectin/metabolism , Thrombin/pharmacology
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