Hypoxic pulmonary vasodilation: a paradigm shift with a hydrogen sulfide mechanism

Abstract

Hypoxic pulmonary vasoconstriction (HVC), an intrinsic and assumed ubiquitous response of mammalian pulmonary blood vessels, matches regional ventilation to perfusion via an unknown O(2)-sensing mechanism. Global pulmonary hypoxia experienced by individuals suffering from chronic obstructive pulmonary disease or numerous hypoventilation syndromes, including sleep apnea, often produces maladaptive pulmonary hypertension, but pulmonary hypertension is not observed in diving mammals, where profound hypoxia is routine. Here we examined the response of cow and sea lion pulmonary arteries (PA) to hypoxia and observed the expected HVC in the former and a unique hypoxic vasodilation in resistance vessels in the latter. We then used this disparate response to examine the O(2)-sensing mechanism. In both animals, exogenous H(2)S mimicked the vasoactive effects of hypoxia in isolated PA. H(2)S-synthesizing enzymes, cystathionine beta-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate sulfur transferase, were identified in lung tissue from both animals by one-dimensional Western blot analysis and immunohistochemistry. The relationship between H(2)S production/consumption and O(2) was examined in real time by use of amperometric H(2)S and O(2) sensors. H(2)S was produced by sea lion and cow lung homogenate in the absence of O(2), but it was rapidly consumed when O(2) was present. Furthermore, consumption of exogenous H(2)S by cow lung homogenate, PA smooth muscle cells, and heart mitochondria was O(2) dependent and exhibited maximal sensitivity at physiologically relevant Po(2) levels. These studies show that HVC is not an intrinsic property of PA and provide further evidence for O(2)-dependent H(2)S metabolism in O(2) sensing.

Hydrogen sulfide as an oxygen sensor

“…Cardiovascular system Identical responses to hypoxia and H 2 S, be it constriction, dilation, or multi-phasic, have been observed in more than 30 studies on isolated vessels, perfused organs, and intact animals encompassing all classes of vertebrates (27,94,123,125,128,129,150,151). Not surprisingly, H 2 S also dilates the mouse ductus arteriosus (5), which would be expected to keep this vessel patent in the relative hypoxic intrauterine environment.…”

“…It is commonly assumed that to accomplish this, systemic vessels dilate in response to hypoxia and pulmonary vessels constrict (155) but this is obviously not consistent throughout vertebrates or even within mammals (129,143).…”

“…Hypoxia appears to increase CBS in the mitochondria (164) and stress-related stimuli can translocate CSE to the mitochondria, although this may take hours (42); additional details are provided in sections ''CBS Translocation to Mitochondria'' and ''CSE Translocation to Mitochondria.'' Initially, it was believed that CBS was predominantly found in the brain and CSE was found in the cardiovascular system [reviewed in Kimura (73)], although a broader distribution is now becoming apparent (6,73,129). H 2 S can also be derived from d-cysteine; however, this appears limited to the brain and kidney, where it protects the former from oxidative stress and the latter from re-perfusion injury (147).…”

“…4) There is relatively little information on the specific Po 2 s at which H 2 S oxidation becomes impaired. We used polarographic H 2 S sensors to monitor the rate of tissue and mitochondrial H 2 S consumption at carefully controlled Po 2 (129). This can then be compared with the Po 2 that produces hypoxic vasoconstriction or the O 2 sensitivity of other putative O 2 -sensing mechanisms.…”

“…Not surprisingly, H 2 S also dilates the mouse ductus arteriosus (5), which would be expected to keep this vessel patent in the relative hypoxic intrauterine environment. Perhaps the strongest argument for the commonality of H 2 S and hypoxia is the observation that both constrict bovine pulmonary arteries, whereas they dilate pulmonary arteries from the sea lion (129) (Fig. 4B).…”