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- Volume 83, 2021
Annual Review of Physiology - Volume 83, 2021
Volume 83, 2021
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The Remarkable Cardiovascular System of Giraffes
Vol. 83 (2021), pp. 1–15More LessGravity affects the physiology of many animals, and the effect is, for good reason, most pronounced in tall species. The physiology—in particular, cardiovascular function—of giraffes has therefore captivated the interest of physiologists for centuries. Several studies document high mean arterial blood pressure of giraffes of about 200 mm Hg. This appears necessary to establish a cerebral perfusion pressure on the order of 100 mm Hg at the cranial end of the carotid arteries. Here, we discuss the unique characteristics of blood vessels, the heart, and the kidney of giraffes and how these functional and structural adaptations are related to very high blood pressure. We also discuss how the cerebral circulation of giraffes is established and what we know about how the blood flow and arterial and venous pressures in giraffes change when they stop to drink and subsequently lift their heads 5–6 m in one sweeping movement.
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Regulation of Hemogenic Endothelial Cell Development and Function
Yinyu Wu, and Karen K. HirschiVol. 83 (2021), pp. 17–37More LessEmbryonic definitive hematopoiesis generates hematopoietic stem and progenitor cells (HSPCs) essential for establishment and maintenance of the adult blood system. This process requires the specification of a subset of vascular endothelial cells to become blood-forming, or hemogenic, and the subsequent endothelial-to-hematopoietic transition to generate HSPCs therefrom. The mechanisms that regulate these processes are under intensive investigation, as their recapitulation in vitro from human pluripotent stem cells has the potential to generate autologous HSPCs for clinical applications. In this review, we provide an overview of hemogenic endothelial cell development and highlight the molecular events that govern hemogenic specification of vascular endothelial cells and the generation of multilineage HSPCs from hemogenic endothelium. We also discuss the impact of hemogenic endothelial cell development on adult hematopoiesis.
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Renal Denervation to Treat Heart Failure
Vol. 83 (2021), pp. 39–58More LessHeart failure (HF) is a global pandemic with a poor prognosis after hospitalization. Despite HF syndrome complexities, evidence of significant sympathetic overactivity in the manifestation and progression of HF is universally accepted. Confirmation of this dogma is observed in guideline-directed use of neurohormonal pharmacotherapies as a standard of care in HF. Despite reductions in morbidity and mortality, a growing patient population is resistant to these medications, while off-target side effects lead to dismal patient adherence to lifelong drug regimens. Novel therapeutic strategies, devoid of these limitations, are necessary to attenuate the progression of HF pathophysiology while continuing to reduce morbidity and mortality. Renal denervation is an endovascular procedure, whereby the ablation of renal nerves results in reduced renal afferent and efferent sympathetic nerve activity in the kidney and globally. In this review, we discuss the current state of preclinical and clinical research related to renal sympathetic denervation to treat HF.
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Cardiac Regeneration: New Hope for an Old Dream
Vol. 83 (2021), pp. 59–81More LessThe regenerative capacity of the heart has long fascinated scientists. In contrast to other organs such as liver, skin, and skeletal muscle, the heart possesses only a minimal regenerative capacity. It lacks a progenitor cell population, and cardiomyocytes exit the cell cycle shortly after birth and do not re-enter after injury. Thus, any loss of cardiomyocytes is essentially irreversible and can lead to or exaggerate heart failure, which represents a major public health problem. New therapeutic options are urgently needed, but regenerative therapies have remained an unfulfilled promise in cardiovascular medicine until today. Yet, through a clearer comprehension of signaling pathways that regulate the cardiomyocyte cell cycle and advances in stem cell technology, strategies have evolved that demonstrate the potential to generate new myocytes and thereby fulfill an essential central criterion for heart repair.
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Dynamics of Atrial Fibrillation Mechanisms and Comorbidities
Vol. 83 (2021), pp. 83–106More LessAtrial fibrillation (AF) contributes to morbidity and mortality of millions of individuals. Its molecular, cellular, neurohumoral, and hemodynamic pathophysiological mechanisms are complex, and there is increasing awareness that a wide range of comorbidities can contribute to AF-promoting atrial remodeling. Moreover, recent research has highlighted that AF risk is not constant and that the temporal variation in concomitant conditions contributes to the complexity of AF dynamics. In this review, we provide an overview of fundamental AF mechanisms related to established and emerging comorbidities or risk factors and their role in the AF-promoting effects. We focus on the accumulating evidence for the relevance of temporally dynamic changes in these risk factors and the consequence for AF initiation and maintenance. Finally, we highlight the important implications for future research and clinical practice resulting from the dynamic interaction between AF risk factors and mechanisms.
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Regulation of Mitochondrial Ca2+ Uptake
Vol. 83 (2021), pp. 107–126More LessMitochondria are responsible for ATP production but are also known as regulators of cell death, and mitochondrial matrix Ca2+ is a key modulator of both ATP production and cell death. Although mitochondrial Ca2+ uptake and efflux have been studied for over 50 years, it is only in the past decade that the proteins responsible for mitochondrial Ca2+ uptake and efflux have been identified. The identification of the mitochondrial Ca2+ uniporter (MCU) led to an explosion of studies identifying regulators of the MCU. The levels of these regulators vary in a tissue- and disease-specific manner, providing new insight into how mitochondrial Ca2+ is regulated. This review focuses on the proteins responsible for mitochondrial transport and what we have learned from mouse studies with genetic alterations in these proteins.
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The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe?
Vol. 83 (2021), pp. 127–151More LessGDF15 is a cell activation and stress response cytokine of the glial cell line–derived neurotrophic factor family within the TGF-β superfamily. It acts through a recently identified orphan member of the GFRα family called GFRAL and signals through the Ret coreceptor. Cell stress and disease lead to elevated GDF15 serum levels, causing anorexia, weight loss, and alterations to metabolism, largely by actions on regions of the hindbrain. These changes restore homeostasis and, in the case of obesity, cause a reduction in adiposity. In some diseases, such as advanced cancer, serum GDF15 levels can rise by as much as 10–100-fold, leading to an anorexia-cachexia syndrome, which is often fatal. This review discusses how GDF15 regulates appetite and metabolism, the role it plays in resistance to obesity, and how this impacts diseases such as diabetes, nonalcoholic fatty liver disease, and anorexia-cachexia syndrome. It also discusses potential therapeutic applications of targeting the GDF15-GFRAL pathway and lastly suggests some potential unifying hypotheses for its biological role.
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The ABCs of Sterol Transport
Vol. 83 (2021), pp. 153–181More LessCholesterol homeostasis and trafficking are critical to the maintenance of the asymmetric plasma membrane of eukaryotic cells. Disruption or dysfunction of cholesterol trafficking leads to numerous human diseases. ATP-binding cassette (ABC) transporters play several critical roles in this process, and mutations in these sterol transporters lead to disorders such as Tangier disease and sitosterolemia. Biochemical and structural information on ABC sterol transporters is beginning to emerge, with published structures of ABCA1 and ABCG5/G8; these two proteins function in the reverse cholesterol transport pathway and mediate the efflux of cholesterol and xenosterols to high-density lipoprotein and bile salt micelles, respectively. Although both of these transporters belong to the ABC family and mediate the efflux of a sterol substrate, they have many distinct differences. Here, we summarize the current understanding of sterol transport driven by ABC transporters, with an emphasis on these two extensively characterized transporters.
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Voltage-Gated Calcium Channels in Nonexcitable Tissues
Vol. 83 (2021), pp. 183–203More LessThe identification of a gain-of-function mutation in CACNA1C as the cause of Timothy syndrome, a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. Previous studies in cells and animal models had suggested that several voltage-gated Ca2+ channels (VGCCs) regulated critical signaling events in various cell types that are not expected to support action potentials, but definitive data were lacking. VGCCs occupy a special position among ion channels, uniquely able to translate membrane excitability into the cytoplasmic Ca2+ changes that underlie the cellular responses to electrical activity. Yet how these channels function in cells not firing action potentials and what the consequences of their actions are in nonexcitable cells remain critical questions. The development of new animal and cellular models and the emergence of large data sets and unbiased genome screens have added to our understanding of the unanticipated roles for VGCCs in nonexcitable cells. Here, we review current knowledge of VGCC regulation and function in nonexcitable tissues and cells, with the goal of providing a platform for continued investigation.
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Temperature Sensation: From Molecular Thermosensors to Neural Circuits and Coding Principles
Rui Xiao, and X.Z. Shawn XuVol. 83 (2021), pp. 205–230More LessTemperature is a universal cue and regulates many essential processes ranging from enzymatic reactions to species migration. Due to the profound impact of temperature on physiology and behavior, animals and humans have evolved sophisticated mechanisms to detect temperature changes. Studies from animal models, such as mouse, Drosophila, and C. elegans, have revealed many exciting principles of thermosensation. For example, conserved molecular thermosensors, including thermosensitive channels and receptors, act as the initial detectors of temperature changes across taxa. Additionally, thermosensory neurons and circuits in different species appear to adopt similar logic to transduce and process temperature information. Here, we present the current understanding of thermosensation at the molecular and cellular levels. We also discuss the fundamental coding strategies of thermosensation at the circuit level. A thorough understanding of thermosensation not only provides key insights into sensory biology but also builds a foundation for developing better treatments for various sensory disorders.
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Olfactory Circuitry and Behavioral Decisions
Vol. 83 (2021), pp. 231–256More LessIn mammals, odor information detected by olfactory sensory neurons is converted to a topographic map of activated glomeruli in the olfactory bulb. Mitral cells and tufted cells transmit signals sequentially to the olfactory cortex for behavioral outputs. To elicit innate behavioral responses, odor signals are directly transmitted by distinct subsets of mitral cells from particular functional domains in the olfactory bulb to specific amygdala nuclei. As for the learned decisions, input signals are conveyed by tufted cells as well as by mitral cells to the olfactory cortex. Behavioral scene cells link the odor information to the valence cells in the amygdala to elicit memory-based behavioral responses. Olfactory decision and perception take place in relation to the respiratory cycle. How is the sensory quality imposed on the olfactory inputs for behavioral outputs? How are the two types of odor signals, innate and learned, processed during respiration? Here, we review recent progress on the study of neural circuits involved in decision making in the mouse olfactory system.
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Cellular Heterogeneity in Adipose Tissues
Vol. 83 (2021), pp. 257–278More LessAdipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although adipocytes make up more than 90% of adipose tissue volume, they represent less than 50% of its cellular content. Here, I review recent advances in genetic lineage tracing and transcriptomics that reveal the identities of the heterogeneous cell populations constituting mouse and human adipose tissues. In addition to mature adipocytes and their progenitors, these include endothelial and various immune cell types that together orchestrate adipose tissue development and functions. One salient finding is the identification of progenitor subtypes that can modulate adipogenic capacity through paracrine mechanisms. Another is the description of fate trajectories of monocyte/macrophages, which can respond maladaptively to nutritional and thermogenic stimuli, leading to metabolic disease. These studies have generated an extraordinary source of publicly available data that can be leveraged to explore commonalities and differences among experimental models, providing new insights into adipose tissues and their role in metabolic disease.
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Brown Adipose Tissue: A Metabolic Regulator in a Hypothalamic Cross Talk?
Vol. 83 (2021), pp. 279–301More LessSince the discovery of functionally competent, energy-consuming brown adipose tissue (BAT) in adult humans, much effort has been devoted to exploring this tissue as a means for increasing energy expenditure to counteract obesity. However, despite promising effects on metabolic rate and insulin sensitivity, no convincing evidence for weight-loss effects of cold-activated human BAT exists to date. Indeed, increasing energy expenditure would naturally induce compensatory feedback mechanisms to defend body weight. Interestingly, BAT is regulated by multiple interactions with the hypothalamus from regions overlapping with centers for feeding behavior and metabolic control. Therefore, in the further exploration of BAT as a potential source of novel drug targets, we discuss the hypothalamic orchestration of BAT activity and the relatively unexplored BAT feedback mechanisms on neuronal regulation. With a holistic view on hypothalamic-BAT interactions, we aim to raise ideas and provide a new perspective on this circuit and highlight its clinical relevance.
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Ceramides in Metabolism: Key Lipotoxic Players
Vol. 83 (2021), pp. 303–330More LessThe global prevalence of metabolic diseases such as type 2 diabetes mellitus, steatohepatitis, myocardial infarction, and stroke has increased dramatically over the past two decades. These obesity-fueled disorders result, in part, from the aberrant accumulation of harmful lipid metabolites in tissues not suited for lipid storage (e.g., the liver, vasculature, heart, and pancreatic beta-cells). Among the numerous lipid subtypes that accumulate, sphingolipids such as ceramides are particularly impactful, as they elicit the selective insulin resistance, dyslipidemia, and ultimately cell death that underlie nearly all metabolic disorders. This review summarizes recent findings on the regulatory pathways controlling ceramide production, the molecular mechanisms linking the lipids to these discrete pathogenic events, and exciting attempts to develop therapeutics to reduce ceramide levels to combat metabolic disease.
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Uterine Excitability and Ion Channels and Their Changes with Gestation and Hormonal Environment
Vol. 83 (2021), pp. 331–357More LessWe address advances in the understanding of myometrial physiology, focusing on excitation and the effects of gestation on ion channels and their relevance to labor. This review moves through pioneering studies to exciting new findings. We begin with the myometrium and its myocytes and describe how excitation might initiate and spread in this myogenic smooth muscle. We then review each of the ion channels in the myometrium: L- and T-type Ca2+ channels, KATP (Kir6) channels, voltage-dependent K channels (Kv4, Kv7, and Kv11), twin-pore domain K channels (TASK, TREK), inward rectifier Kir7.1, Ca2+-activated K+ channels with large (KCNMA1, Slo1), small (KCNN1–3), and intermediate (KCNN4) conductance, Na-activated K channels (Slo2), voltage-gated (SCN) Na+ and Na+ leak channels, nonselective (NALCN) channels, the Na K-ATPase, and hyperpolarization-activated cation channels. We finish by assessing how three key hormones— oxytocin, estrogen, and progesterone—modulate and integrate excitability throughout gestation.
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Hedgehog Signaling in Intestinal Development and Homeostasis
Vol. 83 (2021), pp. 359–380More LessThe hedgehog (Hh) signaling pathway plays several diverse regulatory and patterning roles during organogenesis of the intestine and in the regulation of adult intestinal homeostasis. In the embryo, fetus, and adult, intestinal Hh signaling is paracrine: Hh ligands are expressed in the endodermally derived epithelium, while signal transduction is confined to the mesenchymal compartment, where at least a dozen distinct cell types are capable of responding to Hh signals. Epithelial Hh ligands not only regulate a variety of mesenchymal cell behaviors, but they also direct these mesenchymal cells to secrete additional soluble factors (e.g., Wnts, Bmps, inflammatory mediators) that feed back to regulate the epithelial cells themselves. Evolutionary conservation of the core Hh signaling pathway, as well as conservation of epithelial/mesenchymal cross talk in the intestine, has meant that work in many diverse model systems has contributed to our current understanding of the role of this pathway in intestinal organogenesis, which is reviewed here.
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Sestrins in Physiological Stress Responses
Vol. 83 (2021), pp. 381–403More LessSestrins are a family of proteins that respond to a variety of environmental stresses, including genotoxic, oxidative, and nutritional stresses. Sestrins affect multiple signaling pathways: AMP-activated protein kinase, mammalian target of rapamycin complexes, insulin-AKT, and redox signaling pathways. By regulating these pathways, Sestrins are thought to help adapt to stressful environments and subsequently restore cell and tissue homeostasis. In this review, we describe how Sestrins mediate physiological stress responses in the context of nutritional and chemical stresses (liver), physical movement and exercise (skeletal muscle), and chemical, physical, and inflammatory injuries (heart). These findings also support the idea that Sestrins are a molecular mediator of hormesis, a paradoxical beneficial effect of low- or moderate-level stresses in living organisms.
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Epigenetic Signatures and Plasticity of Intestinal and Other Stem Cells
Vol. 83 (2021), pp. 405–427More LessThe cardinal properties of adult tissue stem cells are self-renewal and the ability to generate diverse resident cell types. The daily losses of terminally differentiated intestinal, skin, and blood cells require “professional” stem cells to produce replacements. This occurs by continuous expansion of stem cells and their immediate progeny, followed by coordinated activation of divergent transcriptional programs to generate stable cells with diverse functions. Other tissues turn over slowly, if at all, and vary widely in strategies for facultative stem cell activity or interconversion among mature resident cell types (transdifferentiation). Cell fate potential is programmed in tissue-specific configurations of chromatin, which restrict the complement of available genes and cis-regulatory elements, hence allowing specific cell types to arise. Using as a model the transcriptional and chromatin basis of cell differentiation and dedifferentiation in intestinal crypts, we discuss here how self-renewing and other tissues execute homeostatic and injury-responsive stem cell activity.
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Function of Renal Nerves in Kidney Physiology and Pathophysiology
Vol. 83 (2021), pp. 429–450More LessRenal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation to treat hypertension have yielded promising results. Therefore, a greater understanding of how renal nerves control the kidney under physiological and pathophysiological conditions is needed. In this review, we provide an overview of the current knowledge of the anatomy of efferent and afferent renal nerves and their functions in normal and pathophysiological conditions. We also suggest further avenues of research for development of novel therapies targeting the renal nerves.
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Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation
Vol. 83 (2021), pp. 451–475More LessAldosterone excess is a pathogenic factor in many hypertensive disorders. The discovery of numerous somatic and germline mutations in ion channels in primary hyperaldosteronism underscores the importance of plasma membrane conductances in determining the activation state of zona glomerulosa (zG) cells. Electrophysiological recordings describe an electrically quiescent behavior for dispersed zG cells. Yet, emerging data indicate that in native rosette structures in situ, zG cells are electrically excitable, generating slow periodic voltage spikes and coordinated bursts of Ca2+ oscillations. We revisit data to understand how a multitude of conductances may underlie voltage/Ca2+ oscillations, recognizing that zG layer self-renewal and cell heterogeneity may complicate this task. We review recent data to understand rosette architecture and apply maxims derived from computational network modeling to understand rosette function. The challenge going forward is to uncover how the rosette orchestrates the behavior of a functional network of conditional oscillators to control zG layer performance and aldosterone secretion.
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Previous Volumes
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Volume 86 (2024)
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Volume 85 (2023)
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Volume 84 (2022)
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Volume 83 (2021)
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Volume 82 (2020)
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Volume 81 (2019)
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Volume 80 (2018)
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Volume 79 (2017)
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Volume 78 (2016)
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Volume 77 (2015)
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Volume 76 (2014)
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Volume 75 (2013)
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Volume 74 (2012)
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Volume 73 (2011)
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Volume 72 (2010)
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Volume 71 (2009)
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Volume 70 (2008)
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Volume 69 (2007)
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Volume 68 (2006)
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Volume 67 (2005)
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Volume 66 (2004)
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Volume 65 (2003)
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Volume 64 (2002)
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Volume 63 (2001)
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Volume 62 (2000)
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Volume 61 (1999)
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Volume 60 (1998)
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Volume 59 (1997)
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Volume 58 (1996)
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Volume 57 (1995)
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Volume 56 (1994)
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Volume 55 (1993)
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Volume 54 (1992)
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Volume 53 (1991)
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Volume 52 (1990)
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Volume 51 (1989)
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Volume 50 (1988)
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Volume 49 (1987)
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Volume 48 (1986)
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Volume 47 (1985)
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Volume 46 (1984)
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Volume 45 (1983)
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Volume 44 (1982)
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Volume 43 (1981)
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Volume 42 (1980)
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Volume 41 (1979)
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Volume 40 (1978)
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Volume 39 (1977)
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Volume 38 (1976)
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Volume 37 (1975)
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Volume 36 (1974)
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Volume 35 (1973)
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Volume 34 (1972)
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Volume 33 (1971)
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Volume 32 (1970)
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Volume 31 (1969)
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Volume 30 (1968)
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Volume 29 (1967)
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Volume 28 (1966)
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Volume 27 (1965)
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Volume 26 (1964)
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Volume 25 (1963)
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Volume 24 (1962)
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Volume 23 (1961)
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Volume 22 (1960)
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Volume 21 (1959)
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Volume 20 (1958)
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Volume 19 (1957)
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Volume 18 (1956)
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Volume 17 (1955)
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Volume 16 (1954)
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Volume 15 (1953)
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Volume 14 (1952)
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Volume 13 (1951)
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Volume 12 (1950)
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Volume 11 (1949)
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Volume 10 (1948)
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Volume 9 (1947)
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Volume 8 (1946)
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Volume 7 (1945)
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Volume 6 (1944)
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Volume 5 (1943)
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Volume 4 (1942)
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Volume 3 (1941)
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Volume 2 (1940)
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Volume 1 (1939)
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Volume 0 (1932)