Cellular and Molecular Mechanisms Associated with Carotid Body Adaptations to Chronic Hypoxia

Abstract

Chronic hypoxia leads to adaptations in the respiratory system manifested as a persistent increase in resting ventilation, termed ventilatory acclimatization to hypoxia (VAH). Increased afferent nerve activity from carotid bodies and the ensuing reflex activation of ventilation are critical for eliciting VAH. In this review we highlight recent information on the cellular and molecular mechanisms associated with chronic hypoxia-induced functional and structural changes in the carotid body. Chronic hypoxia leads to hypersensitivity of the carotid bodies and induces morphological changes, including enlargement of the organ, hyperplasia of glomus cells, and neovascularization. Enhanced hypoxic sensitivity is due to alterations in ion current densities, as well as changes in neurotransmitter dynamics and recruitment of additional neuromodulators (endothelin- 1, ET-1) in glomus cells. Morphological alterations are in part due to upregulation of growth factors (e.g., VEGF). VAH is markedly attenuated in mice partially deficient in HIF-1 transcription factor, which regulates several downstream genes, including VEGF, ET-1, and Ca(2+) channels. The finding that VAH is also blunted in mice deficient in the fosB gene led to the suggestion that the magnitude and time course of VAH depend on complex interactions between more than one transcription factor, resulting in coordinated regulation of several downstream genes and their protein products.

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure

“…In animal models of CIH, sustained increases in the sensitivity to hypoxia in carotid chemoreceptors have been observed (40,41). Reactive oxygen species (39) and local RAS activation (27) in the carotid bodies have been implicated in these peripheral adaptations.…”

Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

“…Decreases in arterial pO 2 are detected rapidly by the carotid body, which stimulates a persistent increase in ventilation, increasing arterial pO 2 and decreasing arterial pCO 2 . 36 Based on the arterial blood gas data, this ventilatory response appears to function normally in AHR WT mice at modest altitude but may not in AHR KO mice. Alternatively, the hypoxemia in AHR KO mice could result from alterations in lung morphology that reduce diffusion capacity or from a ventilation- Figure 5.…”

The influence of chronic hypoxia upon chemoreception

“…More recent experiments show mitochondria in carotid bodies depolarize at O 2 tensions much higher than those causing changes in other cell types, although this may represent modulation by factors such as nitric oxide (NO) instead of unique heme molecules (Donnelly and Carroll, 2005). Experimental evidence also exists for NADPH oxidase and heme oxygenase 2 (HO-2) being involved in O 2 -sensing (Prabhakar and Jacono, 2005).…”