Figure 1. There are 140 million highlanders living above 2,500m. On the very left the barometric pressure and the FiO2 are shown at increasing altitudes. Note that the air’s oxygen concentration always stays at 21%, even at high altitude. The populations are depicted at their average residence altitude and the time since they have occupied that region is given in years. Genetic studies in populations adapted to life at high altitudes, e.g. Tibetans, Andeans, Ethiopians and Kyrgyz, revealed the importance of EPAS1 gene (encodes hypoxia-inducible factor-2α, HIF2α) and EGLN1 gene (encodes hypoxia-inducible factor prolyl hydroxylase 2, PHD2), supporting efforts to pharmacologically manipulate HIF pathway as a treatment for pulmonary hypertension. A schematic on the right shows degradation of hydroxylated HIFα subunits in normoxia via the von-Hippel Lindau (VHL) pathway. In hypoxia, HIFα stabilization and dimerization with HIFβ occurs, together with a histone-acetyltransferase (p300), binds to hypoxia-response elements (HRE) in DNA, initiating or enhancing transcription of target genes. HIF inhibitors (HIFi) with specific activity against HIF-2α are investigated as potential treatment for pulmonary hypertension. PHDi:prolyl hydroxylase inhibitors; FIH: factor inhibiting HIF.