Carotid chemoreceptor “resetting” revisited

Abstract

Carotid body (CB) chemoreceptors transduce low arterial O₂ tension into increased action potential activity on the carotid sinus nerves, which contributes to resting ventilatory drive, increased ventilatory drive in response to hypoxia, arousal responses to hypoxia during sleep, upper airway muscle activity, blood pressure control and sympathetic tone. Their sensitivity to O₂ is low in the newborn and increases during the days or weeks after birth to reach adult levels. This postnatal functional maturation of the CB O₂ response has been termed “resetting” and it occurs in every mammalian species studied to date. The O₂ environment appears to play a key role; the fetus develops in a low O₂ environment throughout gestation and initiation of CB “resetting” after birth is modulated by the large increase in arterial oxygen tension occurring at birth. Although numerous studies have reported age-related changes in various components of the O₂ transduction cascade, how the O₂ environment shapes normal CB prenatal development and postnatal “resetting” remains unknown. Viewing CB “resetting” as environment-driven (developmental) phenotypic plasticity raises important mechanistic questions that have received little attention. This review examines what is known (and not known) about mechanisms of CB functional maturation, with a focus on the role of the O₂ environment.

Introduction

Mammalian life depends on a steady supply of oxygen to tissues to meet cellular metabolic needs, while excess oxygen is highly toxic. Therefore, mammals have developed O₂ sensory systems that operate on multiple levels to optimize cellular O₂ availability and promote tolerance to low O₂ tensions, as well as antioxidant systems to reduce oxygen toxicity. An important generalized oxygen sensing system, operative in every nucleated cell, are the hypoxia-inducible factors (HIF), major regulators of cellular oxygen homeostasis in all metazoan animals. Low oxygen tension increases HIF-1α level, which in turn controls the transcription of hundreds of genes involved in cellular-level adaptations to low oxygen tension (Semenza, 2012, Webb et al., 2009). Other generalized cellular O₂-sensing pathways such as the unfolded protein response, nuclear factor (NF)-kb and the mammalian target of rapamycin (mTOR) promote tolerance to hypoxia by modulating transcription and translation (Dunwoodie, 2009, Gorr et al., 2010). Thus, every nucleated cell in the mammalian body exhibits multiple adaptive responses to hypoxia that aim to minimize the effects of reduced oxygen availability and preserve homeostasis. As tissue O₂ tension depends on oxygen delivery, it is not surprising that mammals have also evolved O₂-regulated control of erythrocyte production, generalized systemic vascular responsiveness to hypoxia and specialized O₂-sensing vascular tissues to regulate blood flow, such as the small pulmonary arteries, fetoplacental arteries and the ductus arteriosus (Semenza, 2011, Waypa and Schumacker, 2010).

In order to ensure optimal oxygen intake, as O₂ needs vary with environment and activity, mammals have developed specialized peripheral arterial chemoreceptor organs that continuously sense arterial blood O₂ tension and directly regulate minute ventilation. The main peripheral arterial O₂ chemoreceptors are the carotid bodies (CB), located bilaterally at the carotid bifurcations. They transduce arterial O₂ levels into action potential activity on carotid sinus nerve afferents, which input via the caudal nucleus tractus solitarii to control minute ventilation and maintain normal ${\text{Pa}}_{{\text{O}}_2}$, increase ventilatory drive in response to hypoxia, mediate arousal responses to hypoxia during sleep and provide important modulation of upper airway muscle activity, blood pressure and sympathetic tone (Iturriaga et al., 2009, Prabhakar and Kumar, 2010, Sinski et al., 2012). Perhaps surprisingly, given their importance in cardiorespiratory control, the carotid body chemoreceptors are not functionally mature at birth and require time, after birth, to reset their O₂ responsiveness to adult-like levels (Gauda et al., 2009).

A key point, which will be emphasized throughout this review, is that postnatal development of CB oxygen sensitivity depends on the O₂ environment; if ${\text{Pa}}_{{\text{O}}_2}$ is increased before birth onset of resetting can be hastened while, if ${\text{Pa}}_{{\text{O}}_2}$ is kept low after birth, resetting can be delayed (Blanco et al., 1988, Sterni et al., 1999). During development, the oxygen environment changes remarkably, from the very low oxygen intrauterine environment of the embryo during the first 10–11 weeks of gestation, to the moderately hypoxic environment of the 2nd and 3rd trimesters of gestation, to the ∼4-fold sudden increase in ${\text{Pa}}_{{\text{O}}_2}$ at birth and the oxygen-rich postnatal environment (Dunwoodie, 2009). The mammalian carotid body forms and undergoes structural maturation in this low O₂ environment. In spite of the low in utero ${\text{P}}_{{\text{O}}_2}$, CB O₂ responsiveness is low in the fetus and will increase only after exposure to the higher ${\text{P}}_{{\text{O}}_2}$ after birth (Blanco et al., 1984, Eden and Hanson, 1987, Hertzberg and Lagercrantz, 1987). Over the last ∼30 years, terminology has evolved describing the carotid chemoreceptors during prenatal development as “set”, analogous to a thermostat, to exhibit minimal activity to the normally low ${\text{Pa}}_{{\text{O}}_2}$ (∼23–25 mmHg) of the fetus. A logical extension of the “thermostat” analogy is that after birth, when ${\text{Pa}}_{{\text{O}}_2}$ is 4-fold higher compared to fetal ${\text{Pa}}_{{\text{O}}_2}$, the carotid chemoreceptors “reset” and sense the postnatal ${\text{Pa}}_{{\text{O}}_2}$ of 80–100 mmHg as “normoxia”. After “resetting”, the range of hypoxia sensitivity shifts such that the ${\text{Pa}}_{{\text{O}}_2}$ of 23–25 mmHg, which elicited minimal CB activity in the fetus, will elicit a brisk increase in carotid sinus nerve activity and would be considered severe hypoxia for an infant.

Although substantial progress has been made in understanding postnatal “resetting” of CB O₂ sensitivity, major questions persist and the fundamental mechanisms underlying dependence on the O₂ environment remain unknown. The goal of this review is to explore further the terminology, concepts, possible mechanisms of “resetting” and the role of the low O₂ environment of the fetus in shaping CB functional development. Although beyond the scope of this review, vascular O₂ sensing, HIF-1, other cellular oxygen-sensing pathways and the effects of altered O₂ environments will be discussed when potentially relevant to CB resetting.