Hypoxia inducible factor (HIF)‐2α is required for the development of the catecholaminergic phenotype of sympathoadrenal cells

AbstractThe basic helix‐loop‐helix transcription factor, hypoxia inducible factor (HIF)‐2α has been implicated in the development of the catecholaminergic phenotype in cells of the sympathoadrenal (SA) lineage; however, the underlying mechanisms and HIF‐2α targets remain unclear. Using an immortalized rat adrenomedullary chromaffin cell line (MAH cells) derived from a fetal SA progenitor, we examined the role of HIF‐2α in catecholamine biosynthesis. Chronic hypoxia (2% O2, 24 h) induced HIF‐2α in MAH cells but expression of the rate‐limiting enzyme, tyrosine hydroxylase (TH) and catecholamine levels were unaltered. Interestingly, HIF‐2α depleted MAH cells showed dramatically lower (5–12 times) levels of dopamine and noradrenaline compared with wild‐type and scrambled controls, even in normoxia (21% O2). This was correlated with a marked reduction in the expression of DOPA decarboxylase (DDC) and dopamine β hydroxylase (DβH) but not TH. Chromatin immunoprecipitation assays revealed that HIF‐2α was bound to the DDC gene promoter which contains two putative hypoxia response elements. These data suggest that a basal level of HIF‐2α function is required for the normal developmental expression of DDC and DβH in SA progenitor cells, and that loss of this function leads to impaired catecholamine biosynthesis.

Hypoxia inducible factor (HIF)‐2α is required for the development of the catecholaminergic phenotype of sympathoadrenal cells Journal Articles