Expressions of angiotensin and cytokine receptors in the paracrine signaling of the carotid body in hypoxia and sleep apnea
Introduction
Arterial chemoreceptors in the carotid body, located bilaterally at the bifurcation of the carotid artery, are responsive to chemical changes in the arterial blood, which are essential to elicit the chemoreflex for the maintenance of the blood gases and pH homeostasis. The carotid body is innervated by chemoafferent fibers of the carotid sinus nerves, which project the sensory activity via the glossopharyngeal nerve to the medullary neurons in the nucleus tractus solitary for eliciting the central efferent outputs of the chemoreflex. Increased central respiratory activities and altered autonomic activities are responsible for the ventilatory and circulatory responses to hypoxia, including but not limited to hyperventilation, bradycardia and redistribution of blood flow to vital organs. Thus, resection of the carotid body greatly diminishes the ventilatory response to hypoxia in human subjects (Teppema and Dahan, 2010).
The carotid chemoreceptor is composed of chemosensitive glomus (type-I) cells apposed to nerve endings of petrosal ganglionic neurons. The glomic clusters are also encompassed by sustentacular (type-II) cells and are proximal to highly dense capillaries supplied with blood perfusion far exceeding the metabolic rate of the carotid body (Gonzalez et al., 1994, Lahiri et al., 2001). Thus, chemical stimuli in the arterial blood and signaling molecules locally produced in the carotid body are within a diffusing distance of equilibrium effecting on the chemosensory component of the carotid body. Chemotransduction is mainly mediated by type-I cells which biosynthesize and release a number of neurotransmitters including acetylcholine, ATP, catacholamines, and also neuromodulators including neuropeptides and adenosine in responding to physiological stimuli including hypoxia, hypercapnia and acidosis (Nurse, 2010). More recently, type-II cells are also believed to play an active role in the local regulation of the chemosensory process, mediated by the ATP release from these cells as a paracrine signal to modulate the activity of type-I cells via purinergic pathways (Nurse, 2014).
Moreover, the carotid chemoreceptor is responsive to circulating hormones including angiotensin II, inflammatory and immunogenic signaling molecules including pro-inflammatory cytokines and lipopolysaccharides (LPS) because the corresponding receptors are expressed in the carotid body. In addition, recent findings suggest that a number of vasoactive peptides, including angiotensin II and endothelin-1, and pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, are produced locally in the carotid body. Evidence suggests that these signaling molecules modulate the activity of the carotid chemoreceptor in a paracrine–autocrine manner (Fung et al., 2014). More importantly, these local mechanisms are regulated by hypoxia, as in sustained hypoxia relevant to the physiological acclimation to altitudes and also in intermittent hypoxia relevant to sleep apnea in disease conditions. Thus it has been recently proposed that alterations of the expression of the receptors of these paracrine–autocrine signaling molecules by hypoxia play roles in the inflammatory response of the carotid body to hypoxia and also in the augmented activity of the carotid chemoreceptor, which could be functionally important in the ventilatory acclimation to hypoxia and also in the pathophysiology of sleep apnea (Fung et al., 2014). This review aims to summarize recent findings in the literature focusing on the hypoxic regulation of the expression of angiotensin and cytokine receptors in the paracrine signaling of the carotid body under hypoxic conditions relevant to sleep apnea.
Section snippets
Expression of angiotensin receptors in the carotid body
Carotid chemoreceptors are responsive to angiotensin II because angiotensin (AT) receptors are expressed in the carotid body. Morphological studies have demonstrated that the AT receptor–ligand binding is present in the carotid body with or without sympathetic or afferent denervation, suggesting the expression of AT1 receptors in the chemosensory component of the carotid body (Allen, 1998). Positive AT1-immunoreactivity is found in the rat carotid body although it is not ubiquitously expressed
Expression of receptors of pro-inflammatory cytokines in the carotid body
The carotid chemoreceptor is responsive to pro-inflammatory cytokines because of the expression of cytokine receptors in the carotid body, which plays a role in the immune-to-brain communication of the inflammatory and infective status (Zapata et al., 2011, Porzionato et al., 2013). It has been shown that IL-1 receptor type I (IL-1r1) is expressed in the type-I cells of the carotid body (Wang et al., 2002, Lam et al., 2008, Lam et al., 2012). The receptor is functional because the outward
Hypoxia upregulates the expression of angiotensin receptors in the carotid body
The mRNA and protein expressions of AT1 and AT2 receptors in the carotid body are significantly increased in the carotid body of rats exposed to sustained hypoxia (10% inspired oxygen for weeks), which are colocalized in type-I cells containing tyrosine hydroxylase (Leung et al., 2000, Fung et al., 2002). The increased expression results in doubling the amount of type-I cells and carotid chemoreceptors responding to angiotensin II to 80% in sustained hypoxia (Leung et al., 2000, Fung et al.,
Hypoxia upregulates expressions of cytokine receptors in the carotid body
Evidence supports that hypoxia regulates the cytokine signaling pathway in the carotid body. It has been reported that plasma levels of cytokines are elevated in altitude natives and subjects sojourning at high altitude under a sustained hypoxic condition (Keatings et al., 1996, Mazzeo et al., 2001, Bucchioni et al., 2003). In patients, chronic inflammation is a clinical manifestation in diseases associated with chronic hypoxemia (Wouters, 2005, Celli and Barnes, 2007). Studies have shown that
Upregulated expression of angiotensin receptors in intermittent hypoxia relevant to sleep apnea
Recurrent episodes of hypopnea or apnea in sleep cause intermittent hypoxia, which significantly contributes to the pathophysiological consequences of sleep apnea (Fletcher, 2001, Del Rio et al., 2010, Dempsey et al., 2010, Prabhakar and Semenza, 2012). Thus, intermittent hypoxia induces significant elevated levels of arterial pressures (Fletcher et al., 1992a, Fletcher et al., 1992b), sympathetic activities (Greenberg et al., 1999, Fletcher, 2003), catecholamines (Bao et al., 1997),
Upregulation of cytokine receptors and cytokines in intermittent hypoxia
The mRNA and protein expressions of IL-1r1, gp130 and TNF-r1 are significantly increased in type-I cells in the carotid body of rats exposed to intermittent hypoxia equivalent to a severe condition of sleep apnea for days to weeks (Del Rio et al., 2012a, Lam et al., 2012). Also intermittent hypoxia induces elevated levels of the expression of IL-1β, IL-6 and TNFα in the carotid body (Del Rio et al., 2012a, Lam et al., 2012). The number of cells with the expression of the cytokine receptors and
Summary and conclusion
Fig. 1 summarizes the role of expressions of angiotensin and cytokine receptors in the carotid body. Firstly these receptors expressed in the chemosensitive cell play functional roles in the carotid chemoreceptor response to circulating angiotensin II and cytokines, which activate the chemoafferent activity and the chemoreflex under disease or infectious conditions. More importantly, these receptors are an integral part of the paracrine signaling pathway in the carotid body regulated by
Acknowledgments
Studies were supported by grants from the Research Grants Council, Hong Kong (HKU 766110M, HKU 7510/06M) and internal funding from the University Research Committee, HKU.
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