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Mitochondrial Fission Protein, DRPI: A New Regulator of VEGF-Induced Angiogenesis

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posted on 01.07.2016, 00:00 by Matthew J. Weist
In endothelial cells (ECs), mitochondria function as signaling organelles that generate reactive oxygen species (ROS) instead of ATP, which is mainly produced through glycolysis. Mitochondria exist in a dynamic balance between the joining, fusion, and separation, fission, of mitochondria. These processes are mainly regulated by mitofusin1/2 (MFN1/MFN2) and dynamin-related protein 1 (Drp1), respectively. The regulation and balance of this relationship is required for normal EC function. Our lab and others reported that ROS, derived from NADPH oxidase or mitochondria (mtROS), play an important role in vascular endothelial growth factor (VEGF)-induced angiogenic responses such as EC migration and proliferation. However, the specific role of Drp1 in VEGF-induced angiogenesis ECs has never been investigated. In this study, we demonstrate that VEGF stimulation in human umbilical vein endothelial cells (HUVECs) increases mitochondrial fission, as measured by mitochondria labeling with a mitochondrial targeted fluorescent vector. Mechanistically, VEGF induces phosphorylation of Drp1 at serine 616 (S616), an activating post translational modification, which is associated with an increase in Drp1 oligomerization and translocation from cytosol to mitochondria. VEGF-induced mtROS, as measured by a mitochondria-targeted redox-sensitive probe, or mitochondria-specific O2- reactive probe, is inhibited by overexpression of dominant negative (DN)-Drp1 (K38A), which blocks Drp1 activity. Functionally, inhibition of Drp1 activity prevented VEGF-induced EC migration and proliferation. Thus, our study offers a novel role of Drp1-mediated mitochondrial fission in VEGF-induced mtROS production and angiogenesis in ECs, which is required for promoting revascularization in ischemic vascular disease.



Ushio-Fukai, Masuko



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University of Illinois at Chicago

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Wary, Kishore Mehta, Dolly

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