Reactive Oxygen Species in Pulmonary Vascular Remodeling

Abstract

The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell (SMC) hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the anti-oxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting co-factor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension.

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

“…SOD provides a cellular defense mechanism by scavenging ROS, which constitutes one of the major defense mechanisms of cells against OS (29). In pathological conditions, such as hypoxia, excessive ROS interact with cellular proteins, lipids and DNA, resulting in oxidative cell and tissue damage, and/or behave as second messengers, promoting pulmonary vascular remodeling (30). Mitochondria are a key site of ROS production, but also represent a target for ROS and are compromised by severe or prolonged oxidative stress; this creates a vicious cycle to amplify mitochondrial ROS, which leads to subsequent mitochondrial dysfunction and oxidant generation (31).…”

Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study

“…In the present study, potential POPH patients exhibited higher AaDO2, suggesting that shunting affects potential POPH pulmonary vessels. The etiological factors of pulmonary hypertension are reported to be inflammation, shear stress, and hypoxia-induced oxidative stress (31). Pulmonary shunting in HPS is accompanied by shear stress and hypoxia in pulmonary vessels, while baseline liver cirrhosis produces inflammatory cytokines.…”

Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension

“…The currently available therapies for PH have not adequately improved patient outcomes; therefore, a better understanding of the mechanisms underlying the development of PH is necessary to develop effective therapeutic approaches (18,26,29). Oxidative stress and reactive oxygen species (ROS) signaling are now recognized to have a critical role in the pathogenesis of human PH and animal models of PH (2,7,8,15). This area of investigation has important translational implications since antioxidant treatments interrupt multiple pathological signaling pathways, but it is complicated by the observations that low levels of ROS are essential to normal cell signaling, and the reactions of ROS are highly compartmentalized.…”