Rearrangement of cell types in the rat carotid body neurogenic niche induced by chronic intermittent hypoxia

Abstract

The carotid body (CB) is a prototypical acute oxygen (O2)‐sensing organ that mediates reflex hyperventilation and increased cardiac output in response to hypoxaemia. CB overactivation, secondary to the repeated stimulation produced by the recurrent episodes of intermittent hypoxia, is believed to contribute to the pathogenesis of sympathetic hyperactivity present in sleep apnoea patients. Although CB functional plasticity induced by chronic intermittent hypoxia (CIH) has been demonstrated, the underlying mechanisms are not fully elucidated. Here, we show that CIH induces a small increase in CB volume and rearrangement of cell types in the CB, characterized by a mobilization of immature quiescent neuroblasts, which enter a process of differentiation into mature, O2‐sensing and neuron‐like, chemoreceptor glomus cells. Prospective isolation of individual cell classes has allowed us to show that maturation of CB neuroblasts is paralleled by an upregulation in the expression of specific glomus cell genes involved in acute O2‐sensing. CIH enhances mitochondrial responsiveness to hypoxia in maturing neuroblasts as well as in glomus cells. These data provide novel perspectives on the pathogenesis of CB‐mediated sympathetic overflow that may lead to the development of new pharmacological strategies of potential applicability in sleep apnoea patients. Key points Obstructive sleep apnoea is a frequent condition in the human population that predisposes to severe cardiovascular and metabolic alterations. Activation of the carotid body, the main arterial oxygen‐sensing chemoreceptor, by repeated episodes of hypoxaemia induces exacerbation of the carotid body‐mediated chemoreflex and contributes to sympathetic overflow characteristic of sleep apnoea patients. In rats, chronic intermittent hypoxaemia induces fast neurogenesis in the carotid body with rapid activation of neuroblasts, which enter a process of proliferation and maturation into O2‐sensing chemoreceptor glomus cells. Maturing carotid body neuroblasts and glomus cells exposed to chronic intermittent hypoxia upregulate genes involved in acute O2 sensing and enhance mitochondrial responsiveness to hypoxia. These findings provide novel perspectives on the pathogenesis of carotid body‐mediated sympathetic hyperactivation. Pharmacological modulation of carotid body fast neurogenesis could help to ameliorate the deleterious effects of chronic intermittent hypoxaemia in sleep apnoea patients.

Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice

“…Notably, the characteristics of Olfr78-deficient glomus cells resemble those of CB neuroblasts; these are immature glomus cell precursors that complete their maturation upon exposure to hypoxia. 17 , 40 Carotid body neuroblasts are weakly TH-positive and have reduced dopamine quantal content and poor secretory activity and responsiveness to hypoxia but maintain responses to other stimuli. In addition, their capacitance (proportional to cell size) is smaller than that of glomus cells and more than 80% of these cells exhibit large Na + currents, a sign of cellular immaturity.…”

“… 30 Remarkably, sympathetic activation and systemic hypertension induced by chronic intermittent hypoxia are reduced in constitutive Olfr78 knockout mice. 13 As that chronic intermittent hypoxia activates the conversion of CB neuroblasts into mature glomus cells, 40 an inhibition of this process could explain the decrease in sympathetic overactivation induced by intermittent hypoxia in constitutive (or global) Olfr78 knockout mice. 13 In closing, we speculate that Olfr78 inhibitors, with a tissue or organ action that is more restricted to the CB than HIF2α inhibitors, 48 , 49 may produce an attenuation of CB activity without entirely abolishing the life-saving responses to hypoxia and hypoglycemia.…”

HIF-1α-Induced Mitophagy Regulates the Regenerative Outcomes of Stem Cells in Fat Transplantation

“…The effects of the hypoxic microenvironment on mitochondria are dependent on the type of hypoxic environment 10 , 11 . In this experiment, we successfully simulated the acute, progressively resolving hypoxic environment by establishing an AFT model in nude mice and observed diminished mitochondrial respiratory function under hypoxic conditions.…”

“…Mitochondria, the organelles responsible for energy metabolism in mammalian cells, are extremely susceptible to and highly reliant on oxygen concentration to conduct physiological functions 8 , 9 . Studies have shown that mitochondria undergo different functional adaptations depending on the type of hypoxia 10 , 11 . On the one hand, the dramatic decrease in intracellular oxygen concentration inhibits oxidative phosphorylation (OXPHOS) in the mitochondria, resulting in a decrease in ATP production and, more importantly, high production of reactive oxygen species (ROS) in the cell, which can damage many organelles or macromolecules and ultimately threaten cell survival 12 .…”

Carotid body contribution to the physio‐pathological consequences of intermittent hypoxia: role of nitro‐oxidative stress and inflammation

“…Recently, Caballero et al. (2023) found that CIH induces a slight increase in the CB volume, and mobilization of immature quiescent neuroblasts that enter a process of differentiation into mature chemoreceptor cells. In addition, they found that CIH enhances mitochondrial responsiveness to hypoxia in maturing neuroblasts as well as in chemoreceptor cells.…”