Abstract
An increase in pulmonary artery pressure is a common observation in
adult mammals exposed to alveolar hypoxia. It is considered a
maladaptive response that places an increased workload on the right
ventricle. The mechanisms initiating and maintaining the elevated
pressure are of considerable interest to understanding pulmonary
vascular homeostasis and developing new treatments for pulmonary
hypertension. In particular, it would be helpful to discover the key
molecules in the integrated vascular response to hypoxia to inform
potential drug targets. One strategy is to take advantage of experiments
of nature; specifically, to understand the molecular basis for the
inter-individual variation in the pulmonary vascular response to acute
and chronic hypoxia. This is the motivation for genetic studies in
populations and animals adapted to life at high altitudes. To date,
these studies highlight the importance of hypoxia-inducible factor 2α
(HIF-2α), encoded by EPAS1, and prolyl hydroxylase domain-containing
protein 2 (PHD), encoded by EGLN1, and support efforts to
pharmacologically manipulate HIF-2 activity as a treatment for pulmonary
hypertension.