PHD2 inactivation in Type I cells drives HIF-2α dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodiesMore about Open Access at the Crick
Authors listJames W Fielding Emma J Hodson Xiaotong Cheng David JP Ferguson Luise Eckardt Julie Adam Philomena Lip Matthew Maton-Howarth Indrika Ratnayaka Christopher W Pugh Keith J Buckler Peter Ratcliffe Tammie Bishop
The carotid body is a peripheral arterial chemoreceptor that regulates ventilation in response to both acute and sustained hypoxia. Type I cells in this organ respond to low oxygen both acutely by depolarization and dense core vesicle secretion and, over the longer term, via cellular proliferation and enhanced ventilatory responses. Using lineage analysis, the present study shows that the Type I cell lineage itself proliferates and expands in response to sustained hypoxia. Inactivation of HIF-2α in Type I cells impairs the ventilatory, proliferative and cell intrinsic (dense core vesicle) responses to hypoxia. Inactivation of PHD2 in Type I cells induces multilineage hyperplasia and ultrastructural changes in dense core vesicles to form paraganglioma-like carotid bodies. These changes, similar to those observed in hypoxia, are dependent on HIF-2α. Taken together, these findings demonstrate a key role for the PHD2-HIF-2α couple in Type I cells with respect to the oxygen sensing functions of the carotid body.
Journal Journal of Physiology
Issue number 18