A new study supports the critical role of hypoxia-inducible factor 2-alpha (HIF2α) in pulmonary arterial hypertension (PAH) pathogenesis and indicates that HIF2α-mediated genes might be useful in the diagnosis of PAH.

Hif2a knockdown regulates multiple biological processes associated with PAH, including but not limited to ‘blood vessel development’ and ‘angiogenesis,’ which were further shown to present among genes upregulated in PAH patient lung tissues,” the study authors explained.

They identified 19 gene ontology (GO) biological processes that were correlated with genes downregulated in Hif2a knockdown cells. All of them were strongly associated with PAH pathogenesis.

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Compared to the controls, 14 of the 19 identified GO terms overlapped with the upregulated GO gene sets in PAH patients’ lung tissues and 13 overlapped with upregulated GO terms in PAH patients’ peripheral blood mononuclear cells.

In addition, the study authors observed a positive correlation between hypoxia and Phd2 deficiency-mediated gene expression profiles in Phd2 knockout mice with spontaneous pulmonary hypertension.

Zhu et al stated, “We investigated gene set expression profile rather than evaluating the expression level of individual genes for a compelling reason: mechanism-associated gene sets are highly reproducible and meaningful in transcriptome research.”


Zhu J, Zhao L, Hu Y, et al. Hypoxia-inducible factor 2-alpha mediated gene sets differentiate pulmonary arterial hypertension. Front Cell Dev Biol. 2021;9:701247. doi:10.3389/fcell.2021.701247