Role for ROS and RNS in Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension

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For over one hundred years, it has been known that during hypoxia or low P02 the systemic arteries dilate to supply more oxygen to the deprived organ, however, on the contrary the pulmonary arteries constrict to balance the ratio of perfusion to ventilation. This phenomenon is generally termed as acute hypoxic pulmonary vasoconstriction. If HPV is prolonged it leads to pulmonary hypertension (PH). PH is characterized by pulmonary arterial vasoconstriction and remodeling. Under physiological conditions, the pulmonary arterial circulation is a high-compliance, low-pressure, low-resistance system, which carries blood into pulmonary microcirculation for gas exchange. Pulmonary artery pressure varies with age, from early childhood to the sixth decade of life, where the upper limit of normal pulmonary arterial pressure is regarded as 20 mmHg. Based on this observation, PH generally is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or 30 mmHg during exercise. Details of PH have been discussed in other chapters; hence we will overview the roles of oxidants in regulating HPV and PH in the next section.

Although the mechanisms responsible for the opposite responses of systemic and pulmonary blood vessels to lowering of Po2 are still not clearly understood, several working hypotheses have been proposed. Changes in the metabolism, loss of autacoids synthesis, and alterations in the ion channel activity has long been considered as a cause of HPV and development of PH (17, 33). As depicted in Figure 2, studies have suggested that generation in PASMC of oxidase- or mitochondrial-derived ROS also play a role in sensing 02 tension and in the genesis ofHPV (33). While the production ofROS in most arteries ceases during hypoxia or graded changes in Po2 tension, a few studies have shown that mitochondrial-derived ROS generation detected by dichlorofluorescein diacetate method is paradoxically elevated in the PASMC, thus facilitating rise in the [Ca2+]i levels, which elicits PA contraction (29, 30). In contrast, a recent study has demonstrated that basal high level of ROS in normoxic condition is significantly reduced in the PA during hypoxia, while it is elevated in the renal artery (19). As ROS levels in the cytosol appear to regulate the gating of Kv channels (32, 37), it has been proposed that loss of mitochondrial-derived ROS production during hypoxia blocks the outward Kv1.5 currents and causes an increase in [Ca2+]j in PASMC thereby contracting the PA under low Po2 conditions (19). Furthermore, inhibition of mitochondrial metabolism by dichloroacetate prevents and reverses PH by restoring expression and function of Kv2.1 channels (20). Inhibition of another glucose metabolic pathway, namely the pentose phosphate pathway, has also been shown to prevent HPV and PH by opening Kv channels (11).

Pulmonary Hypertension Mechanism

Figure 2. Scheme showing the three main proposed hypothesis for redox mechanisms involved in the development of acute hypoxic pulmonary vasoconstriction (HPV) that are currently under investigation. Although ail three hypotheses propose a role for changes in cytosolic hydrogen peroxide [HjOj]c or superoxide [02'"]c derived from either mitochondria or cytosolic NAD(P)H oxidase, the downstream signaling pathways that affects force generation are not yet clearly understood.

Figure 2. Scheme showing the three main proposed hypothesis for redox mechanisms involved in the development of acute hypoxic pulmonary vasoconstriction (HPV) that are currently under investigation. Although ail three hypotheses propose a role for changes in cytosolic hydrogen peroxide [HjOj]c or superoxide [02'"]c derived from either mitochondria or cytosolic NAD(P)H oxidase, the downstream signaling pathways that affects force generation are not yet clearly understood.

Besides the regulation of K+channel activity, changes inPo2 also inactivate the L-type Ca2+ channels in VSMC, which critically contributes to the local regulation of systemic circulation (9). In small PA, hypoxia elicits contraction by a mechanism which increases Ca2+ conductance (14). However, a direct evidence for Po2 modulating voltage-gated Ca2+ channel activity in PASMC indicates longitudinal differences in Ca2+ channel density and 02 sensitivity in myocytes from proximal and distal PA. For example, Ca2+ channels from proximal PA myocyte close and distal PA myocyte open to reduction in P02 (9). Although the role of NAD(P)H oxidase-derived ROS in Po2 sensing and regulation of PA tone is uncertain, 02'- produced by non-phagocytic NAD(P)H oxidase during prolonged hypoxia appears to contribute to the constriction of PA in rabbit lungs (33). On the contrary, NADH oxidase-derived H202 has been shown to be increased in normoxia relative to hypoxia, and to cause PA

relaxation through an increase in cGMP (4,22,35). Whereas, studies on gp9 \phox knockout mouse indicate that the phagocytic NAD(P)H-oxidase does not appear to be an important regulator of pulmonary vascular function (33). The role of other NOX-type NAD(P)H oxidases have not yet been examined. Prolonged hypoxia also activates xanthine oxidase and this activation is a cause for increments in 02" levels in the PA (6). Since ROS generation and PKC activation, the latter being stimulated by oxidants, have been reported to occur simultaneously during hypoxia (6), this implies that PKC may also be involved in initiating HPV through various mechanisms including activation of L-type Ca2+ channels.

As discussed above, redox changes and through their influence on ROS interactions with NO, the regulation of prostaglandins and endothelin-1 synthesis, the modulation of the activation states ofKv and Ca2+ channels, and the control of Ca2+ pump activity by ROS, are able to regulate processes including homeostasis, vascular tone and development of HPV. Loss of endothelial NO production in lungs and isolated PA has been associated with the development of HPV (17). Conditions that elevate the production of02'~, such as hypoxia, may inactivate NO in pulmonary vascular tissue associated with formation and result in oxidant stress including decreased intracellular glutathione levels (25). Besides scavenging NO (which inhibits vascular remodeling), ROS and RNS may deactivate K+ channels and activate hypoxia inducible factor (HIF) (28), both of which are well known to participate in cell proliferation and growth. Additionally, endothelin-1 stimulates PASMC proliferation through induction of 02'"under conditions that increase NAD(P)H oxidase activity (31). Therefore, ROS can further participate in offsetting cell proliferation and apoptosis processes, and promote the remodeling of VSM and progression of PH (Fig. 3).

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