Genetic studies in animals
Studies of animals living at high-altitude (Witt & Huerta-Sanchez, 2019) support the role of EPAS1 in adaptation to hypoxia and have suggested a number of other candidates but apart from studies in the yak and cow, little has been reported that links genetic variants to pulmonary vascular homeostasis.
An advantage of animal studies is the potential to cross-breed strains to isolate the gene of interest. This strategy was used successfully to understand the relative resistance of the rat F344 strain to pulmonary hypertension from chronic hypoxia when compared with the WKY strain (Zhao et al., 2015). Successive backcrossing of offsping from a F344xWKY cross onto the more sensitive WKY parental strain resulted in the introgression of DNA from the F344 strain (carrying the resistance gene) onto the WKY background. Sequencing the introgressed DNA demonstrated a stop-codon in SLC39A12 , which encodes the zinc transporter, ZIP12. Mutation of this gene in the WKY strain rendered the WKY strain more resistant to hypoxia-induced pulmonary hypertension. ZIP12 is over expressed in lungs from patients with PAH and it remains to be seen whether pharmological inhibition of ZIP12 is a therapeutic strategy for these patients. Studies are ongoing to develop pharmacological tools for further experimental studies.