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

Abstract

The HIF-1a 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-a subtypes in intermittent hypoxia (IH), resembling recurrent episodic apnea, are unclear. We hypothesized a divergent role of HIF-a 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-1a, -2a, -3a 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-1a and VEGF expression during IH, despite an increase in the mRNA level of HIF-1a and the prominent increase of volume and expression in the CH group. In contrast, there were increased CB expressions of HIF-2a and -3a, and also ET-1 and TH in both IH and CH groups. Results demonstrated a significant role played by HIF-2a and -3a in the CB response to IH, which could be complementary to the expression and role of HIF-1a under hypoxic conditions. This differential regulation of the HIF-a subtypes and pathways could account for the morphological and neurochemical discrepancy in the CB responses to IH and CH.