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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. [ABSTRACT FROM AUTHOR]

Chronic and intermittent ischemic vascular disorders represent a burgeoning clinical challenge. Previous studies have focused on the idea that therapeutic angiogenesis strategies could alleviate tissue ischemia; however, it is now appreciated that vascular disease is not simply limited to vascular wall cells but also influenced by simultaneously occurring inflammatory responses. Our laboratory has discovered that pharmacological treatment of permanent tissue ischemia with dipyridamole significantly augments ischemic tissue reperfusion, angiogenesis, and arteriogenesis over time. We have found that the beneficial effects of dipyridamole therapy are due to its ability to increase tissue nitric oxide bioavailability that corrects tissue redox imbalance. Importantly, we have also discovered that dipyridamole treatment invoking nitric oxide (NO) production significantly downregulates various innate immune response genes during chronic ischemic tissue injury. These findings demonstrate that dipyridamole-induced production of nitrite/NO significantly decreases inflammatory responses while increasing vascular growth in ischemic tissues. [ABSTRACT FROM AUTHOR]

Background: Hydrogen sulfide (H(2)S) therapy is recognized as a modulator of vascular function during tissue ischemia with the notion of potential interactions of nitric oxide (NO) metabolism. However, little is known about specific biochemical mechanisms or the importance of H(2)S activation of NO metabolism during ischemic tissue vascular remodeling. The goal of this study was to determine the effect of H(2)S on NO metabolism during chronic tissue ischemia and subsequent effects on ischemic vascular remodeling responses., Methods and Results: The unilateral, permanent femoral artery ligation model of hind-limb ischemia was performed in C57BL/6J wild-type and endothelial NO synthase-knockout mice to evaluate exogenous H(2)S effects on NO bioavailability and ischemic revascularization. We found that H(2)S selectively restored chronic ischemic tissue function and viability by enhancing NO production involving both endothelial NO synthase and nitrite reduction mechanisms. Importantly, H(2)S increased ischemic tissue xanthine oxidase activity, hind-limb blood flow, and angiogenesis, which were blunted by the xanthine oxidase inhibitor febuxostat. H(2)S treatment increased ischemic tissue and endothelial cell hypoxia-inducible factor-1α expression and activity and vascular endothelial growth factor protein expression and function in a NO-dependent manner that was required for ischemic vascular remodeling., Conclusions: These data demonstrate that H(2)S differentially regulates NO metabolism during chronic tissue ischemia, highlighting novel biochemical pathways to increase NO bioavailability for ischemic vascular remodeling.