J Appl Physiol 98: 1091, 2005;
doi:10.1152/japplphysiol.01396.2004
8750-7587/05 $8.00
COMMENTARY
HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia
Commentary
With the aim of improving therapies for pulmonary hypertension, much attention has been given to investigating how hypoxia affects the signaling pathways that underlie production of vasoactive substances by the pulmonary vasculature. Previous studies have suggested that pulmonary vascular nitric oxide (NO) signaling is impaired as a result of exposure to in vivo chronic hypoxia, but is restored 3 days after hypoxic exposure. Such studies have influenced explorations of how other signaling pathways contribute to early stages of chronic hypoxia-induced pulmonary hypertension in newborns. In the first featured article, entitled "Cyclooxygenase-2 and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs," Dr. C. Fike and colleagues (1) explored the relationship between the COX-2 pathway of arachidonic acid metabolism and disrupted pulmonary vascular tone regulation in early stages of newborn pulmonary hypertension. These investigators found that COX-2-dependent contracting factors exhibit greater influence on agonist-induced pulmonary arterial responses than COX 2-dependent dilators. Moreover, it appears that other cell types in addition to endothelial cells, including smooth muscle cells, may be sources of COX-2-dependent contracting factors. Resistance level pulmonary arteries from hypertensive piglets treated with COX-2 inhibitors exhibited diminished production of the pulmonary vasoconstrictor thromboxane, without a concomitant decrease in production of the dilator prostacyclin. This discordant effect suggests that levels of COX-1 and prostacyclin synthase are diminished and COX-2 and thromboxane synthase are preserved in the resistance level pulmonary arteries of hypertensive piglets. Together with the results of previous studies, these findings highlight the need to delineate the variable roles of signaling pathways in different stages of hypoxia-induced pulmonary hypertension. Although potential shunting of arachidonic acid toward non-COX-2-mediated pathways and the resulting affect on other vascular beds warrant careful attention (particularly in light of recent concerns about VIOXX), the therapeutic benefit of targeting the COX-2 pathway at early stages of chronic hypoxia pulmonary hypertension in newborns should be given serious consideration.
Chronic obstructive pulmonary diseases, as well as prolonged residence at high altitude, may result in generalized airway hypoxia, eliciting pulmonary arterial hypertension. In the second featured article, entitled "Pressure-induced vascular smooth muscle cell depolarization in pulmonary arteries from control and chronically hypoxic rats does not cause myogenic vasoconstriction," D. J. Naik and colleagues (2) investigated stretch-induced (myogenic) vasoconstriction as a potential component of elevated vascular resistance. Although vascular smooth muscle in the pulmonary arteries of both control rats and rats exposed to 4 wk of chronic hypoxia became depolarized in response to stretch, membrane potential depolarization at each pressure was greater in those animals exposed to hypoxia. Arteries from both groups failed to constrict with increases in intraluminal pressure. Consistent with this finding, intracellular calcium ([Ca2+]i) in vascular smooth muscle cells did not increase with stepwise changes in pressure. To measure the effects of depolarizing stimuli on vascular smooth muscle cell [Ca2+]i, these investigators examined changes in luminal diameter and [Ca2+]i in response to potassium chloride (KCl). Although constriction induced by KCl was similar between groups, increases in vascular smooth muscle cell [Ca2+]i were surprisingly blunted in those animals exposed to chronic hypoxia. These data confirm and extend previous studies of myogenic vasoconstriction in conduit arteries, which showed evidence of a lack of myogenic reactivity in the pulmonary circulation. The blunted increase in vascular smooth muscle cell [Ca2+]i in the arteries of chronically hypoxic rats suggests that hypoxia may impair Ca2+ influx pathways in vascular smooth muscle cells and that changes in Ca2+ sensitivity may be more important in regulating vascular tone after chronic hypoxia. This study is the first to directly assess myogenic vasoconstriction in small intrapulmonary arteries and points to important new areas of investigation to elucidate the mechanisms of altered Ca2+ handling after exposure to chronic hypoxia.
Gary C. Sieck
Journal of Applied Physiology
March 2005, Volume 98
REFERENCES
- Fike CD, Kaplowitz MR, Zhang Y, and Pfister SL. Cyclooxygenase-2 and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. J Appl Physiol 98: 1111–1118, 2005.[Abstract/Free Full Text]
- Naik JS, Earley S, Resta TC, and Walker BR. Pressure-induced vascular smooth muscle cell depolarization in pulmonary arteries from control and chronically hypoxic rats does not cause myogenic vasoconstriction. J Appl Physiol 98: 1119–1124, 2005.[Abstract/Free Full Text]
Copyright © 2005 by the American Physiological Society.
