Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem - PubMed (original) (raw)

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Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem

Jeremy P T Ward et al. Curr Opin Pharmacol. 2009 Jun.

Abstract

Hypoxic pulmonary vasoconstriction (HPV) normally optimises ventilation-perfusion matching in the lung, but leads to pulmonary hypertension (PH) under conditions of global hypoxia. The past few years have provided some major advances in our understanding of this complex phenomenon, but significant controversy remains concerning many of the key underlying mechanisms. On balance, recent evidence is most consistent with an elevation in mitochondria-derived reactive oxygen species as a key event for initiation of HPV, with consequent Ca2+ release from intracellular ryanodine-sensitive stores, although the activation pathways and molecular identity of the associated Ca2+ entry pathways remain unclear. Recent studies have also raised our perception of the critical role played by Rho kinase (ROCK) in both sustained HPV and the development of PH, further promoting ROCK and the pathways regulating its activity and expression as important therapeutic targets.

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Figures

Figure 1

Figure 1. Initiation of HPV

Representation of the Redox, ROS and AMPK hypotheses and their potential signalling pathways lxinking the mitochondrial O2 sensor to the initial and sustained components of HPV. The boxes highlight studies from the last 2 years that lend support to and/or suggest additional pathways for each hypothesis. †: as yet, no mechanisms have been implicated by which the Redox hypothesis could account for identified key components of phase 2 of HPV, notably Ca2+ release from ryanodine-sensitive stores and activation of ROCK (see text). AMPK, AMP-activated kinase; NOX1, NADPH oxidase; PH, chronic hypoxic pulmonary hypertension; ROS, reactive oxygen species.

Figure 2

Figure 2. Ca2+ mobilisation in HPV

Mechanisms that have been implicated in the hypoxia-induced elevation of [Ca2+]i, and their potential signalling pathways. Note that some mechanisms are probably only applicable to one phase of HPV (see text). Not shown for clarity: possibility of functionally different types of SOC and Ca2+ store. Note that Na+ entry via NSCC would also contribute to depolarisation. The boxes highlight studies from the last 2 years that address that pathway or channel. †: action of Mg2+ and ATP on KV channels depends on membrane potential (see text). DAG, diacylglycerol; cADPR, cyclic ADP ribose; depol, depolarization; KV, voltage-gated K+ channels; L-type, voltage-gated Ca2+ channels; NCX, Na+-Ca2+ exchanger; RyR, ryanodine receptors; SOC, store operated channels.

Figure 3

Figure 3. Ca2+ sensitisation and ROCK-mediated pathways in HPV and PH

Mechanisms that have been implicated in the activation and modulation of Ca2+ sensitisation pathways in HPV, and sustained vasoconstriction and vascular remodelling in PH, showing the central role of RhoA and ROCK. Not shown: the influence of ROS, RhoA/ROCK and PKC on the cytoskeleton, which could modulate Ca2+ mobilisation, actin-myosin interactions, and remodelling. The boxes highlight studies from the last 2 years that address that pathway. †: the pathways mediating activation of ROCK via 5-HT1B/1D receptors have not been established, but could include SFK. 5-HT, serotonin, 5-hydroxytryptamine; CaM, Ca2+-calmodulin; ET-1, endothelin-1; Frizzled, Wnt receptor; IPAH, idiopathic pulmonary arterial hypertension; MP, myosin phosphatase; PGF2α, prostaglandin F2α; SERT, serotonin transporter; SFK, src-family kinases; SO, superoxide.

Figure 4

Figure 4

Hypothetical diagram showing the contribution to the hypoxia-induced elevation in pulmonary vascular resistance (PVR) of Ca2+-dependent and -independent vasoconstriction and vascular remodelling. Inhibitors of ROCK or its activation pathways may therefore be of benefit for PH, without significantly impairing acute ventilation-perfusion matching.

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References

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