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1.
Redox Biol ; 19: 22-27, 2018 10.
Article in English | MEDLINE | ID: mdl-30096614

ABSTRACT

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.


Subject(s)
Endothelial Cells/metabolism , Glutathione Disulfide/metabolism , Glutathione/metabolism , Oxidative Stress , Vascular Endothelial Growth Factor Receptor-2/metabolism , Aorta/cytology , Aorta/metabolism , Cell Line , Endothelial Cells/cytology , Humans , Oxidation-Reduction
2.
Microcirculation ; 25(7): e12486, 2018 10.
Article in English | MEDLINE | ID: mdl-29923664

ABSTRACT

OBJECTIVE: Oxidative stress is a central event linked with endothelial dysfunction and inflammation in several vascular pathologies, marked by over-production of ROS and concomitant decreases in antioxidants, for example GSH. Here, we distinguish endothelial oxidative stress regulation and associated functional disparities in the two main vascular conduits, (arteries and veins) following decreases in GSH. METHODS: MAECs and VCECs were used as models of arterial and venular endothelium, respectively, and BSO (0-100 µmol/L) was used to indirectly increase cellular oxidative stress. Inflammatory responses were measured using immune cell attachment and immunoblotting for endothelial cell adhesion molecule (ICAM-1, VCAM-1) expression, altered cell proliferation, and wound healing. RESULTS: MAECs and VCECs exhibited differential responses to oxidative stress produced by GSH depletion with VCECs exhibiting greater sensitivity to oxidative stress. Compared to MAECs, VCECs showed a significantly increased inflammatory profile and a decreased proliferative phenotype in response to decreases in GSH levels. CONCLUSIONS: Arterial and venous endothelial cells exhibit differential responses to oxidant stress, and decreases in GSH:GSSG are more exacerbated in venous endothelial cells. Specific pathogenesis in these vascular conduits, with respect to oxidant stress handling, warrants further study, especially considering surgical interventions such as Coronary artery bypass grafting that use both interchangeably.


Subject(s)
Arteries/pathology , Endothelium, Vascular/metabolism , Oxidative Stress/physiology , Veins/pathology , Cell Proliferation , Cells, Cultured , Endothelium, Vascular/pathology , Glutathione/deficiency , Humans , Inflammation/metabolism , Inflammation/pathology , Oxidation-Reduction
3.
J Appl Physiol (1985) ; 120(2): 263-70, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26384410

ABSTRACT

Molecular oxygen (O2) is an essential component for survival and development. Variation in O2 levels leads to changes in molecular signaling and ultimately affects the physiological functions of many organisms. Nitric oxide (NO) and hydrogen sulfide (H2S) are two gaseous cellular signaling molecules that play key roles in several physiological functions involved in maintaining vascular homeostasis including vasodilation, anti-inflammation, and vascular growth. Apart from the aforementioned functions, NO and H2S are believed to mediate hypoxic responses and serve as O2 chemosensors in biological systems. In this literature review, we briefly discuss NO and H2S and their roles during hypoxia.


Subject(s)
Hydrogen Sulfide/metabolism , Hypoxia/metabolism , Nitric Oxide/metabolism , Oxygen/metabolism , Animals , Biological Availability , Homeostasis/physiology , Humans
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