Interactions between calcium and reactive oxygen species in pulmonary arterial smooth muscle responses to hypoxia

Abstract

In contrast to the systemic vasculature, where hypoxia causes vasodilation, pulmonary arteries constrict in response to hypoxia. The mechanisms underlying this unique response have been the subject of investigation for over 50 years, and still remain a topic of great debate. Over the last 20 years, there has emerged a general consensus that both increases in intracellular calcium concentration and changes in reactive oxygen species (ROS) generation play key roles in the pulmonary vascular response to hypoxia. Controversy exists, however, regarding whether ROS increase or decrease during hypoxia, the source of ROS, and the mechanisms by which changes in ROS might impact intracellular calcium, and vice versa. This review will discuss the mechanisms regulating [Ca 2+ ] i and ROS in PASMCs, and the interaction between ROS and Ca 2+ signaling during exposure to acute hypoxia.

Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension

“…The role of ROS in hypoxic pulmonary vasoconstriction has been controversial [13, 33, 35, 51], though growing support demonstrates that hypoxia stimulates mtROS generation [7, 52] which contributes to vascular dysfunction [31, 32]. Similar to previous studies [21, 38, 53], our confocal microscopy studies confirmed that hypoxia increases mtH 2 O 2 and mtO 2 •− (Fig.…”

“…mtROS levels depend on the rate of O 2 reduction to superoxide (O 2 •− ) and on the activity of mitochondrial antioxidant mechanisms [30]. Increasing evidence indicates that mtROS contribute to endothelial cell dysfunction[31, 32] and alter redox-signaling pathways that modulate vascular tone [33–35] by activating redox-sensitive transcription factors that stimulate Nox expression [15]. Since mitochondrial dysfunction is associated with increased Nox4 expression [25], and mtROS have been shown to stimulate the activity of Noxes [15], we hypothesized that mtROS may stimulate increases in Nox activity in the lung during PH pathogenesis.…”

Endothelial-monocyte-activating polypeptide II induces rat C6 glioma cell apoptosis via the mitochondrial pathway

“…Nevertheless, whether ROS is involved in the processing of EMAP II inducing rat C6 glioma cells apoptosis through mitochondrial pathway is unclear. Increasing evidence suggests that elevation in intracellular Ca 2þ may lead to ROS generation [21,22]. It is reported that EMAP II increased the concentration of intracellular Ca 2þ in endothelial cells [23].…”

The ROS controversy in hypoxic pulmonary hypertension revisited

“…Although there is a global consensus amongst scientists that elevation of the intracellular calcium concentration plays a critical role in producing HPV, the precise underlying mechanisms (e.g. nature of the oxygen sensor, direction of changes in reactive oxygen species (ROS) as well as how ROS production affects the activity of calcium channels) and even the cell type involved remain a subject of ongoing debate [2][3][4].…”

“…Although there is a global consensus amongst scientists that elevation of the intracellular calcium concentration plays a critical role in producing HPV, the precise underlying mechanisms (e.g. nature of the oxygen sensor, direction of changes in reactive oxygen species (ROS) as well as how ROS production affects the activity of calcium channels) and even the cell type involved remain a subject of ongoing debate [2][3][4].Numerous studies have pinpointed the critical implication of ROS in HPV, but controversy remains regarding levels of ROS that mediate HPV [2,5]. Due, at least in part, to the broad range of chemically distinct ROS, their highly reactive nature, as well as differing methods of quantification and models, conflicting results have been reported establishing two partly opposing models.…”