ABSTRACT
Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.
Subject(s)
Disease Models, Animal , Hypoxia , Pulmonary Artery , Sleep Apnea, Obstructive , Vasoconstriction , Animals , Guinea Pigs , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/metabolism , Hypoxia/physiopathology , Hypoxia/metabolism , Pulmonary Artery/physiopathology , Pulmonary Artery/metabolism , Male , Phenylephrine/pharmacology , Vascular Remodeling , Carotid Body/physiopathology , Carotid Body/metabolism , Endothelium, Vascular/physiopathology , Endothelium, Vascular/metabolism , VasodilationABSTRACT
Molecular oxygen suffices the ATP production required for the survival of us aerobic organisms. But it is also true that oxygen acts as a source of reactive oxygen species that elicit a spectrum of damages in living organisms. To cope with such intrinsic ambiguity of biological activity oxygen exerts, aerobic mechanisms are equipped with an exquisite adaptive system, which sensitively detects partial pressure of oxygen within the body and controls appropriate oxygen supply to the tissues. Physiological responses to hypoxia are comprised of the acute and chronic phases, in the former of which the oxygen-sensing remains controversial particularly from mechanistic points of view. Recently, we have revealed that the prominently redox-sensitive cation channel TRPA1 plays key roles in oxygen-sensing mechanisms identified in the peripheral tissues and the central nervous system. In this review, we summarize recent development of researches on oxygen-sensing mechanisms including that in the carotid body, which has been recognized as the oxygen receptor organ central to acute oxygen-sensing. We also discuss how ubiquitously the TRPA1 contributes to the mechanisms underlying the acute phase of adaptation to hypoxia.
Subject(s)
Oxygen , TRPA1 Cation Channel , Transient Receptor Potential Channels , TRPA1 Cation Channel/metabolism , Humans , Oxygen/metabolism , Animals , Transient Receptor Potential Channels/metabolism , Hypoxia/metabolism , Calcium Channels/metabolism , Nerve Tissue Proteins/metabolism , Reactive Oxygen Species/metabolism , Carotid Body/metabolismABSTRACT
The Olfr78 gene encodes a G-protein-coupled olfactory receptor that is expressed in several ectopic sites. Olfr78 is one of the most abundant mRNA species in carotid body (CB) glomus cells. These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in constitutive Olfr78 knockout mice. In another study, constitutive Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. To further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for maturation of glomus cells.
Subject(s)
Carotid Body , Receptors, Odorant , Tyrosine 3-Monooxygenase , Animals , Male , Mice , Carotid Body/metabolism , Hypoxia/metabolism , Hypoxia/genetics , Mice, Inbred C57BL , Mice, Knockout , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Tyrosine 3-Monooxygenase/metabolism , Tyrosine 3-Monooxygenase/geneticsABSTRACT
The carotid body (CB), located bilaterally at the carotid artery bifurcations, is the primary sensory organ for monitoring arterial blood O2 levels. Carotid bodies are immature at birth, exhibiting low sensitivity to hypoxia, and become more sensitive with maturation during the first few weeks of neonatal life. To understand the molecular basis for the postnatal developmental hypoxic responses of CB, we isolated CBs from 5-day and 21-day-old Sprague-Dawley rats and performed RNA sequencing, which allows comprehensive analysis of gene expression. Differentially expressed genes (DEGs) were generated using Edge R, while functional enrichment analysis was performed using gene-set enrichment analysis (GSEA). Analysis of RNA-Seq data showed 2604 DEGs of the total 12,696 genes shared between neonates and adults. Of the 2604 DEGs, 924 genes were upregulated, and 1680 genes were downregulated. Further analysis showed that genes related to oxidative phosphorylation (Ox/phos) and hypoxia-signaling pathways were significantly upregulated in neonatal CBs compared to adult CBs, suggesting a possible link to differential developmental hypoxic responses seen in CB. Genes related to cytokine signaling (INFγ and TNFα) and transcription factors (CREB and NFΚB) mediated pathways were enriched in adult CBs, suggesting that expression of these pathways may be linked to developmental regulation. The RNA-Seq results were verified by analyzing mRNA changes in selected genes by qRT-PCR. Our results of enrichment analysis of biological pathways offer valuable insight into CB hypoxic sensing responses related to the development process.
Subject(s)
Carotid Body , Rats , Animals , Carotid Body/metabolism , Rats, Sprague-Dawley , Gene Expression Profiling , Hypoxia/metabolism , Transcription Factors/metabolismABSTRACT
The present study investigated the localization of the adenosine 5'-diphosphate (ADP)-selective P2Y12 purinoceptors in the rat carotid body using multilabeling immunofluorescence. Punctate immunoreactive products for P2Y12 were distributed in chemoreceptive type I cells immunoreactive to vesicular nucleotide transporter (VNUT) or dopamine beta-hydroxylase, but not in S100B-immunoreactive glial-like type II cells. P2Y12 immunoreactivity was localized in cell clusters containing VNUT-immunoreactive type I cells surrounded by the perinuclear cytoplasm and cytoplasmic processes of type II cells immunoreactive for ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and NTPDase3, which hydrolyze extracellular nucleotide tri- and/or di-phosphates. In ATP bioluminescence assays using carotid bodies, the degradation of extracellular ATP was attenuated in the presence of the selective NTPDases inhibitor ARL67156, suggesting ATP-degrading activity by NTPDases in the tissue. These results suggest that ATP released from type I cells is degraded into ADP and adenosine 5'-monophosphate by NTPDases expressed in type II cells, and that ADP modulates type I cells via P2Y12 purinoceptors.
Subject(s)
Carotid Body , Rats , Animals , Receptors, Purinergic P2Y12 , Nucleotides , Adenosine Triphosphate/metabolism , AdenosineABSTRACT
BACKGROUND: Peripheral blood oxygen monitoring via chemoreceptors in the carotid body (CB) is an integral function of the autonomic cardiorespiratory regulation. The presence of the purinergic P2Y12 receptor (P2Y12R) has been implicated in CB; however, the exact role of the receptor in O2 sensing and signal transduction is unknown. METHODS: The presence of P2Y12R was established by immunoblotting, RT qPCR and immunohistochemistry. Primary glomus cells were used to assess P2Y12R function during hypoxia and hypercapnia, where monoamines were measured by HPLC; calcium signal was recorded utilizing OGB-1 and N-STORM Super-Resolution System. Ingravescent hypoxia model was tested in anaesthetized mice of mixed gender and cardiorespiratory parameters were recorded in control and receptor-deficient or drug-treated experimental animals. RESULTS: Initially, the expression of P2Y12R in adult murine CB was confirmed. Hypoxia induced a P2Y12R-dependent release of monoamine transmitters from isolated CB cells. Receptor activation with the endogenous ligand ADP promoted release of neurotransmitters under normoxic conditions, while blockade disrupted the amplitude and duration of the intracellular calcium concentration. In anaesthetised mice, blockade of P2Y12R expressed in the CB abrogated the initiation of compensatory cardiorespiratory changes in hypoxic environment, while centrally inhibited receptors (i.e. microglial receptors) or receptor-deficiency induced by platelet depletion had limited influence on the physiological adjustment to hypoxia. CONCLUSIONS: Peripheral P2Y12R inhibition interfere with the complex mechanisms of acute oxygen sensing by influencing the calcium signalling and the release of neurotransmitter molecules to evoke compensatory response to hypoxia. Prospectively, the irreversible blockade of glomic receptors by anti-platelet drugs targeting P2Y12Rs, propose a potential, formerly unrecognized side-effect to anti-platelet medications in patients with pulmonary morbidities.
Subject(s)
Carotid Body , Humans , Mice , Animals , Carotid Body/metabolism , Oxygen , Receptors, Purinergic P2Y12/genetics , Receptors, Purinergic P2Y12/metabolism , Calcium/metabolism , Hypoxia/metabolismABSTRACT
Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm-generating region of the medulla oblongata - the preBötzinger complex (preBötC). There is also evidence that astrocytes, non-neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preBötC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preBötC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBötC astrocytes was associated with â¼20% and â¼30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by â¼25%. Bilateral inhibition of RTN neurons transduced to express Gi-coupled designer receptors exclusively activated by designer drug (DREADDGi ) by application of clozapine-N-oxide reduced the CO2 response by â¼20% and â¼40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBötC, inhibition of RTN neurons and carotid body denervation reduced the CO2 -induced respiratory response by â¼70%. These data further support the hypothesis that the CO2 -sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preBötC level, astrocytes modulate the activity of the respiratory network in response to CO2 , either by relaying chemosensory information (i.e. they act as CO2 sensors) or by enhancing the preBötC network excitability to chemosensory inputs. KEY POINTS: This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preBötC in mediating the CO2 -sensitive drive to breathe. The data obtained show that disruption of preBötC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia. These data provide further support for the hypothesis that the CO2 -sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites.
Subject(s)
Carotid Body , Rats , Animals , Carotid Body/physiology , Carbon Dioxide/metabolism , Astrocytes/physiology , Chemoreceptor Cells/metabolism , Respiration , Medulla Oblongata/physiologyABSTRACT
An adequate supply of O2 is essential for the maintenance of cellular activity. Systemic or local hypoxia can be experienced during decreased O2 availability or associated with diseases, or a combination of both. Exposure to hypoxia triggers adjustments in multiple physiological systems in the body to generate appropriate homeostatic responses. However, with significant reductions in the arterial partial pressure of O2, hypoxia can be life-threatening and cause maladaptive changes or cell damage and death. To mitigate the impact of limited O2 availability on cellular activity, O2 chemoreceptors rapidly detect and respond to reductions in the arterial partial pressure of O2, triggering orchestrated responses of increased ventilation and cardiac output, blood flow redistribution and metabolic adjustments. In mammals, the peripheral chemoreceptors of the carotid body are considered to be the main hypoxic sensors and the primary source of excitatory feedback driving respiratory, cardiovascular and autonomic responses. However, current evidence indicates that the CNS contains specialized brainstem and spinal cord regions that can also sense hypoxia and stimulate brain networks independently of the carotid body inputs. In this manuscript, we review the discoveries about the functioning of the O2 chemoreceptors and their contribution to the monitoring of O2 levels in the blood and brain parenchyma and mounting cardiorespiratory responses to maintain O2 homeostasis. We also discuss the implications of the chemoreflex-related mechanisms in paediatric and adult pathologies.
Subject(s)
Carotid Body , Hypoxia , Animals , Humans , Child , Chemoreceptor Cells/physiology , Carotid Body/metabolism , Respiration , Lung , Mammals/metabolism , Oxygen/metabolismABSTRACT
In the carotid body of laboratory rodents, adenosine 5'-triphosphate (ATP)-mediated transmission is regarded as critical for transmission from chemoreceptor type I cells to P2X3 purinoceptor-expressing sensory nerve endings. The present study investigated the distribution of P2X3-immunoreactive sensory nerve endings in the carotid body of the adult male Japanese monkey (Macaca fuscata) using multilabeling immunofluorescence. Immunoreactivity for P2X3 was detected in nerve endings associated with chemoreceptor type I cells immunoreactive for synaptophysin. Spherical or flattened terminal parts of P2X3-immunoreactive nerve endings were in close apposition to the perinuclear cytoplasm of synaptophysin-immunoreactive type I cells. Immunoreactivity for ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2), which hydrolyzes extracellular ATP, was localized in the cell body and cytoplasmic processes of S100B-immunoreactive cells. NTPDase2-immunoreactive cells surrounded P2X3-immunoreactive terminal parts and synaptophysin-immunoreactive type I cells, but did not intrude into attachment surfaces between terminal parts and type I cells. These results suggest ATP-mediated transmission between type I cells and sensory nerve endings in the carotid body of the Japanese monkey, as well as those of rodents.
Subject(s)
Carotid Body , Rats , Animals , Male , Carotid Body/metabolism , Macaca fuscata/metabolism , Receptors, Purinergic P2X3/metabolism , Synaptophysin/metabolism , Rats, Wistar , Sensory Receptor Cells/metabolism , Adenosine Triphosphate/metabolismABSTRACT
Heart failure is associated with multiple mechanisms, including sympatho-excitation, and is one of the leading causes of death worldwide. Enhanced carotid body chemoreflex function is strongly related to excessive sympathetic nerve activity and sleep-disordered breathing in heart failure. How to reduce the excitability of the carotid body is still scientifically challenging. Both clinical and experimental evidence have suggested that targeting purinergic receptors is of great potential to combat heart failure. In a recent study, Lataro et al. (Lataro et al. in Nat Commun 14:1725, 5) demonstrated that targeting purinergic P2X3 receptors in the carotid body attenuates the progression of heart failure. Using a series of molecular, biochemical, and functional assays, the authors observed that the carotid body generates spontaneous, episodic burst discharges coincident with the onset of disordered breathing in male rats with heart failure, which was generated by ligating the left anterior descending coronary artery. Moreover, P2X3 receptor expression was found to be upregulated in the petrosal ganglion chemoreceptive neurons of rats with heart failure. Of particular note, treatment with a P2X3 antagonist rescued pathological breathing disturbances, abolished episodic discharges, reinstated autonomic balance, attenuated cardiac dysfunction, and reduced the immune cell response and plasma cytokine levels in those rats.
Subject(s)
Carotid Body , Heart Failure , Rats , Male , Animals , Carotid Body/metabolism , Receptors, Purinergic P2X/metabolism , Heart Failure/metabolism , Neurons/metabolism , Sympathetic Nervous System , Receptors, Purinergic P2X3/metabolism , Receptors, Purinergic P2X2/metabolismABSTRACT
The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPRb) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Leprb, Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Leprb, Trpm7, or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Leprb, Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Leprb, Trpm7, and Insr.NEW & NOTEWORTHY This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.
Subject(s)
Carotid Body , Hyperglycemia , Hypertension , Insulin Resistance , Insulins , TRPM Cation Channels , Male , Mice , Animals , Leptin , Blood Glucose/metabolism , Carotid Body/metabolism , Mice, Obese , TRPM Cation Channels/metabolism , Liver Glycogen/metabolism , Hyperglycemia/metabolism , Obesity/metabolism , Glucose/metabolism , Hypertension/metabolism , Denervation , Insulins/metabolismSubject(s)
Carotid Body , Chemoreceptor Cells , Humans , Chemoreceptor Cells/physiology , Carotid Body/physiology , Oxygen , Hypoxia , Carbon DioxideABSTRACT
The carotid body is a major peripheral chemoreceptor that senses changes in arterial blood oxygen, carbon dioxide, and pH, which is important for the regulation of breathing and cardiovascular function. The mechanisms by which the carotid body senses O2 and CO2 are well known; conversely, the mechanisms by which it senses pH variations are almost unknown. Here, we used immunohistochemistry to investigate how the human carotid body contributes to the detection of acidosis, analyzing whether it expresses acid-sensing ion channels (ASICs) and determining whether these channels are in the chemosensory glomic cells or in the afferent nerves. In ASIC1, ASIC2, and ASIC3, and to a much lesser extent ASIC4, immunoreactivity was detected in subpopulations of type I glomus cells, as well as in the nerves of the carotid body. In addition, immunoreactivity was found for all ASIC subunits in the neurons of the petrosal and superior cervical sympathetic ganglia, where afferent and efferent neurons are located, respectively, innervating the carotid body. This study reports for the first time the occurrence of ASIC proteins in the human carotid body, demonstrating that they are present in glomus chemosensory cells (ASIC1 < ASIC2 > ASIC3 > ASIC4) and nerves, presumably in both the afferent and efferent neurons supplying the organ. These results suggest that the detection of acidosis by the carotid body can be mediated via the ASIC ion channels present in the type I glomus cells or directly via sensory nerve fibers.
Subject(s)
Acidosis , Carotid Body , Humans , Acid Sensing Ion Channels/metabolism , Carotid Body/metabolism , Chemoreceptor Cells/metabolism , Peripheral Nervous System/metabolism , Acidosis/metabolismABSTRACT
The purpose of the present study was to explore the role of carotid body metabotropic glutamate receptor 1 (mGluR1) in chronic intermittent hypoxia (CIH)-induced carotid body plasticity. Sprague Dawley (SD) rats were exposed to CIH (6%-21% O2, 4 min/cycle, 8 h/day) for 4 weeks. The blood pressure of rats was monitored non-invasively by tail-cuff method under consciousness. RT-qPCR was used to examine the mRNA expression level of mGluR1 in rat carotid body. Western blot was used to detect the protein expression level of mGluR1 in rat carotid body. The role of mGluR1 in CIH-induced carotid body sensory long-term facilitation (sLTF) was investigated by ex vivo carotid sinus nerve discharge recording, and the carotid body sLTF was evoked by a 10-episode of repetitive acute intermittent hypoxia (AIH: 1 min of 5% O2 interspersed with 5 min of 95% O2). The results showed that: 1) CIH increased the systolic blood pressure (P < 0.001), diastolic blood pressure (P < 0.005) and mean arterial blood pressure (P < 0.001) of rats; 2) CIH decreased the mRNA and protein levels of mGluR1 in the rat carotid body (P < 0.01); 3) 4 weeks of CIH induced carotid body sLTF significantly, exhibiting as an increasing baseline sensory activity during post-AIH, which was inhibited by application of an agonist of group I metabotropic glutamate receptors, (S)-3,5-dihydroxyphenylglycine (DHPG), during sLTF induction (P < 0.005). In summary, these results suggest that activation of mGluR1 inhibits CIH-induced carotid body plasticity in rats.
Subject(s)
Carotid Body , Receptors, Metabotropic Glutamate , Rats , Animals , Carotid Body/metabolism , Rats, Sprague-Dawley , Hypoxia , Receptors, Metabotropic Glutamate/metabolism , RNA, Messenger/metabolismABSTRACT
The carotid body (CB) is a polymodal chemosensory organ that plays an essential role in initiating respiratory and cardiovascular adjustments to maintain blood gas homeostasis. Much of the available evidence suggests that chronic hypoxia induces marked morphological and neurochemical changes within the CB, but the detailed molecular mechanisms by which these affect the hypoxic chemosensitivity still remain to be elucidated. Dysregulation of the CB function and altered oxygen saturation are implicated in various physiological and pathophysiological conditions. Knowledge of the morphological and functional aspects of the CB would improve our current understanding of respiratory and cardiovascular homeostasis in health and disease.
Subject(s)
Carotid Body , Humans , Carotid Body/physiology , Chemoreceptor Cells/physiology , Hypoxia , Arteries , HeartABSTRACT
This chapter describes the history of the carotid body (CB) and the subsequent research on its structure and function. The chronological development of ideas about its anatomical structure as a ganglion, the first descriptions of its glandular nature as a ball of highly vascular tissue (glomus), the discovery of its neural crest origin and relevant embryological views as a true paraganglion toward a more conclusive understanding of its sensory nature as a chemoreceptor for chemical changes in blood have been consistently demonstrated. The knowledge of the CB neurochemistry, physiology and pathophysiology has progressed immensely in the past century and a large and compelling body of evidence for the presence of a neurogenic niche in the CB has accumulated over the last two decades, thus underlying its function and possibility for the development of cell replacement therapies.
Subject(s)
Carotid Body , Paraganglia, Chromaffin , Carotid Body/physiology , Chemoreceptor Cells , NeurogenesisABSTRACT
The carotid body (CB) is the main peripheral arterial chemoreceptor that registers the levels of pO2, pCO2 and pH in the blood and responds to their changes by regulating breathing. It is strategically located in the bifurcation of each common carotid artery. The organ consists of "glomera" composed of two cell types, glomus and sustentacular cells, interspersed by blood vessels and nerve bundles and separated by connective tissue. The neuron-like glomus or type I cells are considered as the chemosensory cells of the CB. They contain numerous cytoplasmic organelles and dense-cored vesicles that store and release neurotransmitters. They also form both conventional chemical and electrical synapses between each other and are contacted by peripheral nerve endings of petrosal ganglion neurons. The glomus cells are dually innervated by both sensory nerve fibers through the carotid sinus nerve and autonomic fibers of sympathetic origin via the ganglioglomerular nerve. The parasympathetic efferent innervation is relayed by vasomotor fibers of ganglion cells located around or inside the CB. The glial-like sustentacular or type II cells are regarded to be supporting cells although they sustain physiologic neurogenesis in the adult CB and are thus supposed to be progenitor cells as well. The CB is a highly vascularized organ and its intraorgan hemodynamics possibly plays a role in the process of chemoreception.
Subject(s)
Carotid Body , Animals , Carotid Body/metabolism , Chemoreceptor Cells/physiology , Neurons , Carotid Artery, Common , Ganglia , MammalsABSTRACT
The mammalian carotid body (CB) exhibits considerable plasticity of its structure during development and aging and as a consequence of environmental, metabolic and inflammatory stimuli. The structural changes during maturation include an enlargement of the total and vascular volume of the CB. Conversely, aging results in a reduction in the number and volume of glomus cells with progressive cellular degeneration and an apparent increase in the surrounding connective tissue. Age-related structural alterations are similar to those during chronic hypoxia. Long-term hypoxic exposure and sodium nitrate treatment enlarge several-fold the size of the rat CB causing glomus cell hypertrophy and hyperplasia, and evoke changes in its vascular structure, inducing marked vasodilation and neovascularization. In humans, such structural CB adaptation responses to prolonged hypoxia occur during acclimatization to high altitudes. On the other hand, the hyperoxic CB is significantly smaller than those of age-matched normoxic controls. Morphological alterations in the CB in both hypertensive animals and humans are characterized by a slightly enlarged parenchyma without apparent vascular expansion and/or dilation. The CB structural plasticity depends on the existence of a population of multipotent neural crest-derived stem cells, which are activated during hypoxia to proliferate and differentiate into new both neuronal (glomus) and vascular cell types.