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Regulation of Mitochondrial Fragmentation in Microvascular Endothelial Cells Isolated from the Su5416/Hypoxia model ...

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#1 Engadin

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Posted 03 September 2019 - 11:17 AM


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E N T I R E   T I T L E :   Regulation of Mitochondrial Fragmentation in Microvascular Endothelial Cells Isolated from the Su5416/Hypoxia model of Pulmonary Arterial Hypertension

 

 

 

Originally posted by 'macrohistory' here.

 

B E H I N D   P A Y W A L L  S O U R C E :   American Journal of Physiology 

 

 

 

 

 

Abstract

 

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by progressive right ventricle (RV) failure due to elevated pulmonary artery pressures (PAP). In PAH, histologically complex vaso-occlusive lesions in the pulmonary vasculature contribute to elevated PAP. However, the mechanisms underlying dysfunction of the microvascular endothelial cells (MVECs) that comprise a significant portion of these lesions are not well understood. We recently showed that MVECs isolated from the rat Sugen/Hypoxia (SuHx) experimental model of PAH (SuHx-MVECs) exhibit increases in: migration/proliferation, mitochondrial ROS (mtROS) production, intracellular calcium levels ([Ca2+]i) and mitochondrial fragmentation. Furthermore, quenching mtROS with the targeted antioxidant MitoQ attenuated basal [Ca2+]I, migration and proliferation; however, whether increased mtROS was associated with increased [Ca2+]i and/or changes in mitochondrial morphology was not clear. To better understand this relationship, we measured changes in mitochondrial morphology at baseline and following inhibition of mtROS with the targeted antioxidant MitoQ and Ca2+ entry, by inhibiting the Ca2+ channel TRPV4. Quenching mtROS or inhibiting TRPV4 attenuated fragmentation in SuHx-MVECs. Conversely, inducing mtROS production in MVECs from normoxic rats (N-MVECs) increased fragmentation. Ca2+ entry induced by treatment with the TRPV4 agonist, GSK1017920A, was significantly increased in SuHx-MVECs and was attenuated with MitoQ treatment. Basal and maximal respiration were depressed in SuHx-MVECs, and inhibiting mtROS but not TRPV4 improved respiration in these cells. Our data show that, in SuHx-MVECs, mtROS production promotes: a) TRPV4-mediated increases in [Ca2+]i; b) mitochondrial fission and c) decreased mitochondrial respiration, suggesting an important role for mtROS in driving MVEC dysfunction in PAH.

 

 

 

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