Neurosci. Bull. February, 2019, 35(1):98–112 www.neurosci.cn https://doi.org/10.1007/s12264-018-0274-y www.springer.com/12264 REVIEW Cellular and Molecular Mechanisms Underlying Arterial Baroreceptor Remodeling in Cardiovascular Diseases and Diabetes 1 1 1 Huiyin Tu • Dongze Zhang • Yu-Long Li Received: 15 March 2018 / Accepted: 31 May 2018 / Published online: 27 August 2018 Ó Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018 Abstract Clinical trials and animal experimental studies to and from the cells in the body through the blood. Its have demonstrated an association of arterial baroreflex function is to maintain homeostasis and provide adequate impairment with the prognosis and mortality of cardiovas- nourishment for fighting various types of diseases. The cular diseases and diabetes. As a primary part of the arterial arterial baroreflex plays an important role in regulating the baroreflex arc, the pressure sensitivity of arterial barore- cardiovascular system [1, 2]. In general, when arterial ceptors is blunted and involved in arterial baroreflex vascular tension triggers a feedback signal, the arterial dysfunction in cardiovascular diseases and diabetes. baroreflex reflexively decreases the excessive arterial blood Changes in the arterial vascular walls, mechanosensitive pressure and heart rate to the normal physiological range. ion channels, and voltage-gated ion channels contribute to The arterial baroreflex arc is composed of an afferent limb the attenuation of arterial baroreceptor sensitivity. Some (baroreceptor neurons), a central component (central endogenous substances (such as angiotensin II and super- nuclei), and an efferent limb (peripheral sympathetic and oxide anion) can modulate these morphological and parasympathetic neurons). Arterial baroreceptors, includ- functional alterations through intracellular signaling path- ing carotid and aortic baroreceptors, are key afferents of ways in impaired arterial baroreceptors. Arterial barore- the baroreflex arc. The cell bodies of these baroreceptors ceptors can be considered as a potential therapeutic target are located in the nodose and petrosal ganglia and their to improve the prognosis of patients with cardiovascular terminals innervate arterial blood vessels in the carotid diseases and diabetes. sinus and aortic arch. These terminals sense mechanical changes of the arterial vasculature in the carotid sinus and Keywords Cardiovascular disease Á Diabetes Á Baroreflex Á aortic arch and produce excitatory electrical signals, which Baroreceptor Á Vascular wall Á Mechanosensitive ion are integrated and modulated in the arterial baroreceptors channels Á Voltage-gated ion channels Á Angiotensin II Á by local modulators. Then the integrated signal is conveyed Superoxide Á Nuclear factor-kappa B to the dorsal medial region of the nucleus of the solitary tract (a central component of the baroreflex arc) in the dorsal medulla. Finally, this excitation evokes peripheral Introduction sympathoinhibitory and parasympathoexcitatory responses. Therefore, the consequence of arterial baroreceptor acti- With neurohormonal regulation, the cardiovascular system vation is to decrease heart rate, cardiac output, and primarily transports substances such as amino-acids, elec- peripheral vascular resistance, and to reflexively neutralize trolytes, O2,CO2, hormones, and other metabolic products an increase in arterial blood pressure and heart rate [3–5]. Cardiovascular diseases (such as heart failure and hypertension) and diabetes are major health problems & Yu-Long Li worldwide [6–8], especially cardiovascular diseases that [email protected] are the number-one killer in the USA [6]. Attenuation of 1 Department of Emergency Medicine, University of Nebraska arterial baroreflex sensitivity is considered to be a common Medical Center, Omaha, NE 68198, USA feature in cardiovascular diseases and diabetes [9–15]. 123 H. Tu et al.: Baroreceptors in Cardiovascular Diseases and Diabetes 99 Much evidence indicates that decreased baroreflex sensi- the regulation of cardiopulmonary function or blood tivity leads to cardiac arrhythmogenesis and sudden cardiac volume, low-pressure baroreceptors are located in the death [1, 16, 17], and is linked with the prognosis and great systemic veins, pulmonary arteries, and walls of right mortality in patients with cardiovascular diseases or and left atria. diabetes [18–22]. The baroreflex can be modulated by Arterial baroreceptors, one type of pseudo-unipolar regulatory circuitry at multiple levels including peripheral peripheral neurons, have a special structural feature. Each nerve afferents at the baroreceptors, central components, soma of the arterial baroreceptors in the nodose and and efferent components (sympathetic and parasympathetic petrosal ganglia has an initial axon segment that bifurcates nerves). In the baroreflex arc, structural and functional into two processes [33, 34]. changes in each component may attenuate the baroreflex One process is defined as the central process, which sensitivity. However, two pieces of evidence should be terminates in the dorsomedial region of the nucleus of the considered. First, recent studies have confirmed that solitary tract [33, 34], while the other is the peripheral arterial baroreflex dysfunction is attributable to functional process, which innervates the arterial vasculature in the impairment of the baroreceptors under pathophysiological aortic arch and carotid sinus [33, 34]. The structure of the conditions [4, 23–28]. Second, both animal studies and aortic baroreceptor neuron is illustrated in Fig. 1. clinical trials have demonstrated that baroreceptor activa- The structure of the nerve terminals in the peripheral tion therapy (direct electrical stimulation of the barorecep- process innervating the arterial vasculature has been tor area) markedly attenuates the symptoms and improves extensively studied using light and electron microscopic the prognosis in cardiovascular diseases and diabetes techniques [35–42]. Although there are subtle differences [18, 20, 22, 29, 30]. Therefore, baroreceptor impairment among species, the common morphological features are as might be an important factor in baroreflex dysfunction, follows [35, 36, 41]. First, unmyelinated and myelinated including peripheral sympathetic over-activation and with- fibers in these nerve bundles form a network that pursues a drawal of peripheral parasympathetic activity in cardio- roughly helical course in the adventitia, and also reaches vascular diseases and diabetes. Direct electrical stimulation of the baroreceptor area is a novel therapeutic approach for patients with cardiovascular diseases or diabetes, and has a strong pathophysiological rationale. However, the surgical procedure for baroreceptor stimulation can have adverse complications, including nerve injury, hematoma, head- ache, worsening of existing heart failure, and hypertension [30–32]. Considering these sequelae, exploring the cellular and molecular mechanism(s) associated with the impair- ment of arterial baroreceptors and identifying effective therapeutic interventions are crucial for improving the development and prognosis of patients with cardiovascular diseases and diabetes. In this review, we mainly discuss the pathophysiological changes of arterial baroreceptors and related mechanisms in cardiovascular diseases and diabetes. Anatomy and Physiology of Arterial Baroreceptors Baroreceptors are divided into high-pressure arterial baroreceptors and low-pressure baroreceptors. High-pres- sure arterial baroreceptors, also known as arterial barore- ceptors, have stretch-sensitive terminals, and mainly innervate arterial vasculature in the aortic arch and carotid sinus. Arterial baroreceptors are an important part of the negative feedback regulation of blood pressure and heart rate, although low-pressure baroreceptors also influence Fig. 1 Cartoon of an aortic baroreceptor neuron including a soma, a blood pressure by adjusting blood volume and the retention central process to the NTS (nucleus of the solitary tract), and a of salt and water in the kidney. As the main receptors for peripheral process to the aortic arch. 123 100 Neurosci. Bull. February, 2019, 35(1):98–112 the border of the media to form complex, irregular carotid baroreceptors are embedded in vascular wall varicosities (rings or reticula). Second, the afferent axons components that include elastin, collagen, and smooth contain abundant neurotubules. Third, densely-packed muscle cells. This specific structure ensures viscoelastic mitochondria occur in most of the nerve terminals. Fourth, coupling between arterial vascular wall components and axoplasmic organelles accumulate in varicosities of the the terminals of arterial baroreceptors. Deformation of the lanceolate terminals, including granular vesicles, glycogen baroreceptor terminals is triggered by mechanical disten- particles, lamellated bodies, and lysosomes. Considering sion of the arterial vasculature when blood pressure rises. the fast response of electrical impulses to pulsatile arterial Mechanoelectrical transduction is the second step: expansion, the presence of numerous mitochondria in the mechanosensitive ion channels are activated by deforma- nerve terminals supports the high metabolic rate of arterial tion of the baroreceptor terminals, inducing their depolar- baroreceptors [35, 36, 41]. Granular vesicles, neurotubules, ization. This completes the conversion from mechanical to glycogen particles, lamellated bodies, and lysosomes