Impact of Mitochondria and NADPH Oxidases on Acute and Sustained Hypoxic Pulmonary Vasoconstriction

Abstract

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation to optimize pulmonary gas exchange. However, it remains unclear whether acute HPV (occurring within seconds) and the vasoconstrictor response to sustained alveolar hypoxia (developing over several hours) are triggered by identical mechanisms. We investigated the effect of mitochondrial and NADPH oxidase inhibitors on both phases of HPV in intact rabbit lungs. These studies revealed that the sustained HPV is largely dependent on mitochondrial complex I and totally dependent on complex IV, whereas NADPH oxidase dependence was only observed for acute HPV. These findings were reinforced by an alternative approach employing lungs from mice deficient in the NADPH oxidase subunit p 47(phox). In these mice (which lack a subunit suggested to be important for the function of most NADPH oxidase isoforms), but not in gp 91(phox)-deficient mice (which represent only one isoform of NADPH oxidases), acute HPV was significantly reduced, while non-hypoxia-induced vasoconstrictions elicited by the thromboxane mimetic U46619 were not affected. We concluded that the acute phase and the sustained phase of HPV are differentially regulated, with NADPH oxidase activity predominating in the acute phase, while a strong dependence on mitochondrial participation was observed for the second phase.

Mitochondrial cytochrome redox states and respiration in acute pulmonary oxygen sensing

“…As no such difference was detected at higher oxygen concentrations, this supports the hypothesis that NADPH oxidases are active even at very low oxygen concentrations and thus their activity can also contribute to the regulation of HPV. This is in line with the previous finding in intact lungs [9].…”

“…Such responses occur at O 2 levels below a PO 2 of 20-50 mmHg [3][4][5]. Mitochondria, as the primary O 2 -consuming organelle of the cell, have long been thought to play a key role in the O 2 sensing process of HPV, with recent new findings stimulating this field of research [6][7][8][9]. Mitochondria use oxygen for energy production by transferring electrons along an energy gradient onto oxygen.…”

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

“…Studies using a genetic knockout of p47 phox suggest that cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase systems may also contribute to the HPV response during acute hypoxia (40). The blockade of hypoxia-induced ROS responses we observe with depletion of RISP suggests that the mitochondria may act as the initiators of ROS production, which could be amplified by engagement of nonphagocytic nicotinamide adenine dinucleotide phosphate reduced oxidase systems elsewhere in the cell.…”

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

“…Therefore, the apparently conflicting conclusions concerning ROS in HPV may be explained by the hypothesis that a local, subcellular and compartmentalised regulation of ROS triggers HPV. This may also be true for the intact organ where a clear majority of investigations demonstrate a decrease in ROS, measured with different methods, although evidence for increased ROS was obtained when some of the ROS-generating systems were blocked (table 1) [103]. Moreover, recent findings of enrichment of ion channels in membrane microdomains may also support the theory of compartimentalisation [104].…”

“…However, since exposure of PAs to prolonged hypoxia may cause ATP-sensitive potassium channels to open due to ATP depletion, the balance of energy state may be incompletely achieved [120]. This may explain the higher sensitivity of HPV to mitochondrial inhibition during prolonged hypoxia [103]. A hint at some potential inhibition of the mitochondrial respiratory chain during hypoxia is the high NADH/nicotinamide adenine dinulceotide (NAD) ratio during acute hypoxia (15-18 mmHg (1.99-2.39 kPa)) [119], but not the NADPH/NADP ratio (35-60 mmHg (4.66-7.99 kPa)) [117] in isolated PAs.…”