Differential expressions and roles of hypoxia-inducible factor-1alpha, -2alpha and -3alpha in the rat carotid body during chronic and intermittent hypoxia.

The HIF-1alpha expression in the carotid body (CB) is central to the transcriptional regulation of the CB structural and functional changes in chronic hypoxia (CH). The CB plays pathogenic roles in cardiovascular morbidity in patients with sleep-disordered breathing; yet, the expression and role of HIF-alpha subtypes in intermittent hypoxia (IH), resembling recurrent episodic apnea, are unclear. We hypothesized a divergent role of HIF-alpha subtypes, regulated by differential expression in the CB response to IH. A time-course analysis of the CB volume, and expression profiles of the HIF-1alpha, -2alpha, -3alpha and HIF-regulated gene products, including vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and tyrosine hydroxylase (TH), showed a significant difference in the lack of increase in the rat CB volume, HIF-1alpha and VEGF expression during IH, despite an increase in the mRNA level of HIF-1alpha and the prominent increase of volume and expression in the CH group. In contrast, there were increased CB expressions of HIF-2alpha and -3alpha, and also ET-1 and TH in both IH and CH groups. Results demonstrated a significant role played by HIF-2alpha and -3alpha in the CB response to IH, which could be complementary to the expression and role of HIF-1alpha under hypoxic conditions. This differential regulation of the HIF-alpha subtypes and pathways could account for the morphological and neurochemical discrepancy in the CB responses to IH and CH.