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Antioxidants 2017, 6(3), 49;

Vitamin C and Microvascular Dysfunction in Systemic Inflammation

Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
Department of Medical Biophysics, University of Western Ontario, London, ON N6A 5C1, Canada
Received: 6 June 2017 / Revised: 26 June 2017 / Accepted: 27 June 2017 / Published: 29 June 2017
(This article belongs to the Special Issue Vitamin C: Current Concepts in Human Physiology)
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Sepsis, life-threatening organ dysfunction caused by a dysfunctional host response to infection, is associated with high mortality. A promising strategy to improve the outcome is to inject patients intravenously with ascorbate (vitamin C). In animal models of sepsis, this injection improves survival and, among others, the microvascular function. This review examines our recent work addressing ascorbate’s ability to inhibit arteriolar dysfunction and capillary plugging in sepsis. Arteriolar dysfunction includes impaired vasoconstriction/dilation (previously reviewed) and impaired conduction of vasoconstriction/dilation along the arteriole. We showed that ascorbate injected into septic mice prevents impaired conducted vasoconstriction by inhibiting neuronal nitric oxide synthase-derived NO, leading to restored inter-endothelial electrical coupling through connexin 37-containing gap junctions. Hypoxia/reoxygenation (confounding factor in sepsis) also impairs electrical coupling by protein kinase A (PKA)-dependent connexin 40 dephosphorylation; ascorbate restores PKA activation required for this coupling. Both effects of ascorbate could explain its ability to protect against hypotension in sepsis. Capillary plugging in sepsis involves P-selectin mediated platelet-endothelial adhesion and microthrombi formation. Early injection of ascorbate prevents capillary plugging by inhibiting platelet-endothelial adhesion and endothelial surface P-selectin expression. Ascorbate also prevents thrombin-induced platelet aggregation and platelet surface P-selectin expression, thus preventing microthrombi formation. Delayed ascorbate injection reverses capillary plugging and platelet-endothelial adhesion; it also attenuates sepsis-induced drop in platelet count in systemic blood. Thrombin-induced release of plasminogen-activator-inhibitor-1 from platelets (anti-fibrinolytic event in sepsis) is inhibited by ascorbate pH-dependently. Thus, under acidotic conditions in sepsis, ascorbate promotes dissolving of microthrombi in capillaries. We propose that protected/restored arteriolar conduction and capillary bed perfusion by ascorbate contributes to reduced organ injury and improved survival in sepsis. View Full-Text
Keywords: sepsis; microvessels; endothelial cells; platelets; electrical coupling; connexins; nitric oxide; P-selectin; coagulation; plasminogen-activator-inhibitor-1 sepsis; microvessels; endothelial cells; platelets; electrical coupling; connexins; nitric oxide; P-selectin; coagulation; plasminogen-activator-inhibitor-1
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Tyml, K. Vitamin C and Microvascular Dysfunction in Systemic Inflammation. Antioxidants 2017, 6, 49.

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