What is the topic of this review? This review is principally concerned with results from studies of the pulmonary vasculature in humans, particularly in relation to
hypoxia and
rare diseases that affect
oxygen sensing. What advances does it highlight? This review highlights the degree to which the
hypoxia-inducible factor (HIF) transcription system influences human pulmonary vascular responses to
hypoxia. Upregulation of the HIF pathway augments hypoxic pulmonary vasoconstriction, while alterations to the pathway found in Tibetans are associated with suppression of the progressive increase in pulmonary artery pressure with sustained
hypoxia. It also highlights the potential importance of
iron, which modulates the HIF pathway, in modifying the pulmonary vascular response to
hypoxia. The human pulmonary circulation loses its natural distensibility during sustained
hypoxia, leading to
pulmonary arterial hypertension and a much higher workload for the right ventricle. The
hypoxia-inducible factor (HIF) pathway is implicated in this pulmonary vascular response to continued
hypoxia by animal studies, and additionally, by rare human diseases where the pathway is upregulated. However, there are no known human
genetic diseases downregulating HIF. Tibetans, though, demonstrate blunted pulmonary vascular responses to sustained
hypoxia. This seems to be accounted for by an altered HIF pathway as a consequence of natural selection over a period of many thousands of years lived at high altitude. In addition to genetic differences,
iron is another important modulator of HIF pathway function. Experimental work in humans demonstrates that manipulation of
iron stores can influence the behaviour of the pulmonary circulation during
hypoxia, in ways analogous to that seen in Tibetans and patients with
rare diseases that affect
oxygen sensing. The importance of physiological differences in
iron bioavailability in modulating hypoxic pulmonary vasoconstriction in health and disease is yet to be established.