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LETTER TO THE EDITOR
Berchner-Pfannschmidt, Acker, and Fandrey (1) point out that the regulation of HIF-1 during hypoxia is equally controversial, with evidence for direct effects via prolyl-hydroxylases and mediation via both elevations and falls in reactive oxygen species (ROS). However, there is no reason to believe that the mechanisms underlying hypoxic pulmonary vasoconstriction (HPV) are necessarily the same as those regulating hypoxia-inducible factor-1 (HIF-1). Indeed, hypoxia increases HIF-1 levels in cell types that do not show the characteristic elevation of cytosolic Ca2+ concentration ([Ca2+]i) seen in pulmonary artery during HPV. This was the point of my original response; the effect of ROS on HIF-1 cannot be used to support either side of the argument as far as HPV is concerned. They also raise an important concept, that of cytosolic O2 availability, which along with ROS production may be altered by modulators of oxidative phosphorylation, such as NO (4).
This has other implications. Weir and Archer (5) in their original response comment that the PO2 commonly used in reductionist preparations is more severe than in vivo and may therefore not be relevant. It is well known that the fall in PO2 required to elicit HPV or elevation of [Ca2+]i becomes greater as one descends from the animal to perfused lungs to isolated arteries to cells. One explanation for this may be that as one progresses through these models there is progressively less NO produced as shear stress is reduced or abolished, so there is less competition between NO and O2 at the cytochrome oxidase, effectively requiring a greater fall in PO2 to have the same effect on electron transport (e.g., see Refs. 1, 4).
Gupte and Wolin (1) put the case for an NADPH oxidase-mediated fall in ROS, with inhibition of guanylate cyclase and inhibition of vasodilatation. However, HPV is not abolished (in mice at least) when either the gp91phox or p47phox subunits are knocked out (2, 6). Moreover, Gupte et al. have shown that hypoxia increases soluble guanylate cyclase activity in rat pulmonary artery (3), which seems difficult to correlate with the above hypothesis. Perhaps cows differ from rats. ... Note that they also imply that all work supporting mitochondria and an elevation in ROS has been performed in large pulmonary arteries or cultured cells. Not so; our studies at least are performed exclusively in small distal arteries!
Both Packer and Pelaez (1) and Evans and Gonzalez (1) are concerned about the response to peroxide (although for different reasons) and its divergence from HPV. I can only refer them back to my original text and reiterate that in our hands low concentrations of oxidants (that do not kill the artery) show similarities to hypoxia in that they cause Ca2+-dependent vasoconstriction in small pulmonary arteries, but vasodilatation in systemic arteries. The fact that the constriction is endothelium independent is interesting but largely irrelevant, as our primary concern here is with pathways leading to elevation of smooth muscle cell [Ca2+]i. The endothelium may differ.
Finally, and in response to my original opponents, the fact that something is difficult to explain does not mean that it does not happen!
REFERENCES
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