Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells
The angiogenic capacity of local tissue critically regulates the response to ischemic injury. Elevated reactive oxygen species production, commonly associated with ischemic injury, has been shown to promote phosphorylation of the vascular endothelial growth factor receptor 2 (VEGFR2), a critical reg...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-10-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231718303744 |
| _version_ | 1811229235984990208 |
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| author | Priya K. Prasai Bandana Shrestha A. Wayne Orr Christopher B. Pattillo |
| author_facet | Priya K. Prasai Bandana Shrestha A. Wayne Orr Christopher B. Pattillo |
| author_sort | Priya K. Prasai |
| collection | DOAJ |
| description | The angiogenic capacity of local tissue critically regulates the response to ischemic injury. Elevated reactive oxygen species production, commonly associated with ischemic injury, has been shown to promote phosphorylation of the vascular endothelial growth factor receptor 2 (VEGFR2), a critical regulator of angiogenesis. Previous data from our lab demonstrated that diminished levels of the antioxidant glutathione positively augment ischemic angiogenesis. Here, we sought to determine the relationship between glutathione levels and oxidative stress in VEGFR2 signaling. We reveal that decreasing the ratio of GSH to GSSG with diamide leads to enhanced protein S-glutathionylation, increased reactive oxygen species (ROS) production, and enhanced VEGFR2 activation. However, increasing ROS alone was insufficient in activating VEGFR2, while ROS enhanced VEGF-stimulated VEGFR2 activation at supraphysiological levels. We also found that inhibiting glutathione reductase activity is sufficient to increase VEGFR2 activation and sensitizes cells to ROS-dependent VEGFR2 activation. Taken together, these data suggest that regulation of the cellular GSH:GSSG ratio critically regulates VEGFR2 activation. This work represents an important first step in separating thiol mediated signaling events from ROS dependent signaling. |
| first_indexed | 2024-04-12T10:11:09Z |
| format | Article |
| id | doaj.art-72c56e16426a4083988671e8eafe8698 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-12T10:11:09Z |
| publishDate | 2018-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-72c56e16426a4083988671e8eafe86982022-12-22T03:37:19ZengElsevierRedox Biology2213-23172018-10-01192227Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cellsPriya K. Prasai0Bandana Shrestha1A. Wayne Orr2Christopher B. Pattillo3Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USADepartment of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USADepartment of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USADepartment of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; Correspondence to: LSU Health Sciences Center – Shreveport, 1501 Kings Hwy, Shreveport, LA 71130, USA.The angiogenic capacity of local tissue critically regulates the response to ischemic injury. Elevated reactive oxygen species production, commonly associated with ischemic injury, has been shown to promote phosphorylation of the vascular endothelial growth factor receptor 2 (VEGFR2), a critical regulator of angiogenesis. Previous data from our lab demonstrated that diminished levels of the antioxidant glutathione positively augment ischemic angiogenesis. Here, we sought to determine the relationship between glutathione levels and oxidative stress in VEGFR2 signaling. We reveal that decreasing the ratio of GSH to GSSG with diamide leads to enhanced protein S-glutathionylation, increased reactive oxygen species (ROS) production, and enhanced VEGFR2 activation. However, increasing ROS alone was insufficient in activating VEGFR2, while ROS enhanced VEGF-stimulated VEGFR2 activation at supraphysiological levels. We also found that inhibiting glutathione reductase activity is sufficient to increase VEGFR2 activation and sensitizes cells to ROS-dependent VEGFR2 activation. Taken together, these data suggest that regulation of the cellular GSH:GSSG ratio critically regulates VEGFR2 activation. This work represents an important first step in separating thiol mediated signaling events from ROS dependent signaling.http://www.sciencedirect.com/science/article/pii/S2213231718303744 |
| spellingShingle | Priya K. Prasai Bandana Shrestha A. Wayne Orr Christopher B. Pattillo Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells Redox Biology |
| title | Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells |
| title_full | Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells |
| title_fullStr | Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells |
| title_full_unstemmed | Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells |
| title_short | Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells |
| title_sort | decreases in gsh gssg activate vascular endothelial growth factor receptor 2 vegfr2 in human aortic endothelial cells |
| url | http://www.sciencedirect.com/science/article/pii/S2213231718303744 |
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