Oxygen-sensing pathways and the pulmonary circulation

The unique property of the pulmonary circulation to constrict in response to hypoxia, rather than dilate, brings advantages in both health and disease. Hypoxic pulmonary vasoconstriction (HPV) acts to optimise ventilation-perfusion matching - this is important clinically both in focal disease (such as pneumonia) and in one-lung ventilation during anaesthesia for thoracic surgery. However, during global hypoxia such as that encountered at high altitude, generalised pulmonary vasoconstriction can lead to pulmonary hypertension. There is now a growing body of evidence that links the hypoxia-inducible factor (HIF) pathway and pulmonary vascular tone - in both acute and chronic settings. Genetic and pharmacological alterations to all key components of this pathway (VHL - von Hippel-Lindau ubiquitin E3 ligase; PHD2 - prolyl hydroxylase domain protein 2; HIF1 and HIF2) have clear effects on the pulmonary circulation, particularly in hypoxia. Furthermore, knowledge of the molecular biology of the prolyl hydroxylase enzymes has led to an extensive and ongoing body of research into the importance of iron in both HPV and pulmonary hypertension. This review will explore these relationships in more detail and discuss future avenues of research.image Abstract figure legend The heterodimeric transcription factor HIF (hypoxia-inducible factor) is thought to be responsible for the majority of adaptive transcriptional changes that take place in response to hypoxia. The stability of the HIF-alpha subunits is regulated by oxygen-dependent prolyl hydroxylation (by prolyl hydroxylase domain proteins, PHDs), which enables recognition by the von Hippel-Lindau (VHL) ubiquitin E3 ligase with subsequent degradation by the ubiquitin-proteasome pathway. In hypoxia, this process is impaired. There is now a growing body of evidence that links the HIF pathway and pulmonary vascular tone - in both acute and chronic settings. Genetic and pharmacological alterations to all key components of this pathway (VHL, PHD2, HIF1 and HIF2) have clear effects on the pulmonary circulation, particularly in hypoxia. Knowledge of the molecular biology of the prolyl hydroxylase enzymes has also led to an ongoing body of research into the importance of iron in both hypoxic pulmonary vasoconstriction and pulmonary hypertension.image

Automated summary

The unique property of the pulmonary circulation to constrict in response to hypoxia plays an important role in optimizing ventilation-perfusion matching. There is growing evidence linking the HIF pathway and pulmonary vascular tone in both acute and chronic settings. Research on the prolyl hydroxylase enzymes has also shed light on the importance of iron in hypoxic pulmonary vasoconstriction and pulmonary hypertension.