What does this research mean for the field?

Reactive oxygen species (ROS) mediate the development of chronic hypoxia-induced pulmonary hypertension by augmenting pulmonary arterial constriction through potentiated calcium influx and myofilament sensitization. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

Synthesize current evidence on the vascular sources of reactive oxygen species and their mechanistic roles in mediating pulmonary vasoconstriction during chronic hypoxia.

October 15, 2020AntioxidantsOpen Access

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

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Why the study?

Understanding the mechanisms by which reactive oxygen species enhance pulmonary vasoconstriction is needed to evaluate the efficacy of antioxidants for treating pulmonary hypertension.

Key Points

Synthesize current evidence on the vascular sources of reactive oxygen species and their mechanistic roles in mediating pulmonary vasoconstriction during chronic hypoxia.
Reviewed cellular sources of reactive oxygen species in pulmonary vasculature, including NADPH oxidases, mitochondria, uncoupled endothelial nitric oxide synthase, and xanthine oxidase.
Analyzed literature on oxidant-mediated functional modifications of calcium and potassium channels, Rho kinase signaling, and preclinical antioxidant trials in animal models.
Chronic hypoxia enhances vascular reactive oxygen species generation while diminishing antioxidant scavenging, stimulating sustained calcium influx and calcium sensitization.
Oxidant signaling alters the conductance of potassium and calcium channels and activates Rho kinase, sustaining severe vasoconstriction in pulmonary arterial smooth muscle cells.
Treatment with diverse antioxidant agents consistently attenuates vasoconstriction and ameliorates vascular remodeling across multiple animal models of pulmonary hypertension.

Structured PICO

Population

Animal models and patients with chronic hypoxia-induced pulmonary hypertension

This review highlights the critical role of reactive oxygen species in mediating enhanced pulmonary vasoconstriction during chronic hypoxia, suggesting antioxidants as a potential therapeutic strategy for pulmonary hypertension.

Implication

Antioxidant strategies merit targeted trials in hypoxic pulmonary hypertension; leaves open proof of clinical benefit.

Abstract

Elevated resistance of pulmonary circulation after chronic hypoxia exposure leads to pulmonary hypertension. Contributing to this pathological process is enhanced pulmonary vasoconstriction through both calcium-dependent and calcium sensitization mechanisms. Reactive oxygen species (ROS), as a result of increased enzymatic production and/or decreased scavenging, participate in augmentation of pulmonary arterial constriction by potentiating calcium influx as well as activation of myofilament sensitization, therefore mediating the development of pulmonary hypertension. Here, we review the effects of chronic hypoxia on sources of ROS within the pulmonary vasculature including NADPH oxidases, mitochondria, uncoupled endothelial nitric oxide synthase, xanthine oxidase, monoamine oxidases and dysfunctional superoxide dismutases. We also summarize the ROS-induced functional alterations of various Ca2+ and K+ channels involved in regulating Ca2+ influx, and of Rho kinase that is responsible for myofilament Ca2+ sensitivity. A variety of antioxidants have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, supporting the role of ROS in the development of pulmonary hypertension. A better understanding of the mechanisms by which ROS enhance vasoconstriction will be useful in evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension.