Thin Air, Thick Vessels: Historical and Current Perspectives on Hypoxic Pulmonary Hypertension

Abstract

The association between pulmonary hypertension (PH) and hypoxia is well-established, with two key mechanistic processes, hypoxic pulmonary vasoconstriction and hypoxia-induced vascular remodeling, driving changes in pulmonary arterial pressure. In contrast to other forms of pulmonary hypertension, the vascular changes induced by hypoxia are reversible, both in humans returning to sea-level from high altitude and in animal models. This raises the intriguing possibility that the molecular drivers of these hypoxic processes could be targeted to modify pulmonary vascular remodeling in other contexts. In this review, we outline the history of research into PH and hypoxia, before discussing recent advances in our understanding of this relationship at the molecular level, focussing on the role of the oxygen-sensing transcription factors, hypoxia inducible factors (HIFs). Emerging links between HIF and vascular remodeling highlight the potential utility in inhibiting this pathway in pulmonary hypertension and raise possible risks of activating this pathway using HIF-stabilizing medications.

Keywords: altitude; hypoxia; hypoxic pulmonary vasoconstriction (HPV); pulmonary hypertension; vascular remodeling.

Figure 1

Pulmonary vascular responses to hypoxia with emphasis on the role of HIF isoforms in remodeling. The right upper branch of this vessel depicts vasoconstriction in acute hypoxia, occurring due to alterations in redox and NO signaling and release of vasoactive mediators. The lower branch indicates remodeling in the context of sustained hypoxic exposure and illustrates HIF-dependent processes revealed by tissue-specific deletion of HIF-isoforms in endothelial cells (HIF-2α) or smooth muscle cells (HIF-1α). Below the vessel, a schematic shows degradation of hydroxylated HIF-α subunits in normoxia via the von-Hippel Lindau (VHL) pathway. In hypoxia or following treatment with prolyl hydroxylase inhibitors (PHDi), HIF-α stabilization and dimerization with HIF-β occurs, leading to transcription of target genes. HIF inhibitors (HIFi) with specific activity against HIF-2α are in clinical development.