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  • Microglia in Physiology and Disease
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Susanne A. Wolf, H.W.G.M. Boddeke, Helmut Kettenmann

    As the immune-competent cells of the brain, microglia play an increasingly important role in maintaining normal brain function. They invade the brain early in development, transform into a highly ramified phenotype, and constantly screen their environment. Microglia are activated by any type of pathologic event or change in brain homeostasis. This activation process is highly diverse and depends on the context and type of the stressor or pathology. Microglia can strongly influence the pathologic outcome or response to a stressor due to the release of a plethora of substances, including cytokines, chemokines, and growth factors. They are the professional phagocytes of the brain and help orchestrate the immunological response by interacting with infiltrating immune cells. We describe here the diversity of microglia phenotypes and their responses in health, aging, and disease. We also review the current literature about the impact of lifestyle on microglia responses and discuss treatment options that modulate microglial phenotypes.

    更新日期:2017-09-26
  • Mechanisms of Organ Injury and Repair by Macrophages*
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Kevin M. Vannella, Thomas A. Wynn

    Macrophages regulate tissue regeneration following injury. They can worsen tissue injury by producing reactive oxygen species and other toxic mediators that disrupt cell metabolism, induce apoptosis, and exacerbate ischemic injury. However, they also produce a variety of growth factors, such as IGF-1, VEGF-α, TGF-β, and Wnt proteins that regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation, and angiogenesis. Proresolving macrophages in turn restore tissue homeostasis by functioning as anti-inflammatory cells, and macrophage-derived matrix metalloproteinases regulate fibrin and collagen turnover. However, dysregulated macrophage function impairs wound healing and contributes to the development of fibrosis. Consequently, the mechanisms that regulate these different macrophage activation states have become active areas of research. In this review, we discuss the common and unique mechanisms by which macrophages instruct tissue repair in the liver, nervous system, heart, lung, skeletal muscle, and intestine and illustrate how macrophages might be exploited therapeutically.

    更新日期:2017-09-26
  • Macrophages and the Recovery from Acute and Chronic Inflammation
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Kajal Hamidzadeh, Stephen M. Christensen, Elizabeth Dalby, Prabha Chandrasekaran, David M. Mosser

    In recent years, researchers have devoted much attention to the diverse roles of macrophages and their contributions to tissue development, wound healing, and angiogenesis. What should not be lost in the discussions regarding the diverse biology of these cells is that when perturbed, macrophages are the primary contributors to potentially pathological inflammatory processes. Macrophages stand poised to rapidly produce large amounts of inflammatory cytokines in response to danger signals. The production of these cytokines can initiate a cascade of inflammatory mediator release that can lead to wholesale tissue destruction. The destructive inflammatory capability of macrophages is amplified by exposure to exogenous interferon-γ, which prolongs and heightens inflammatory responses. In simple terms, macrophages can thus be viewed as incendiary devices with hair triggers waiting to detonate. We have begun to ask questions about how these cells can be regulated to mitigate the collateral destruction associated with macrophage activation.

    更新日期:2017-09-26
  • Macrophage Polarization
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Peter J. Murray

    Macrophage polarization refers to how macrophages have been activated at a given point in space and time. Polarization is not fixed, as macrophages are sufficiently plastic to integrate multiple signals, such as those from microbes, damaged tissues, and the normal tissue environment. Three broad pathways control polarization: epigenetic and cell survival pathways that prolong or shorten macrophage development and viability, the tissue microenvironment, and extrinsic factors, such as microbial products and cytokines released in inflammation. A plethora of advances have provided a framework for rationally purifying, describing, and manipulating macrophage polarization. Here, I assess the current state of knowledge about macrophage polarization and enumerate the major questions about how activated macrophages regulate the physiology of normal and damaged tissues.

    更新日期:2017-09-26
  • Senescence in COPD and Its Comorbidities
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Peter J. Barnes

    Chronic obstructive pulmonary disease (COPD) is regarded as a disease of accelerated lung aging. This affliction shows all of the hallmarks of aging, including telomere shortening, cellular senescence, activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence, and a low-grade chronic inflammation (inflammaging). Many of these pathways are driven by chronic exogenous and endogenous oxidative stress. There is also a reduction in antiaging molecules, such as sirtuins and Klotho, which further accelerate the aging process. COPD is associated with several comorbidities (multimorbidity), such as cardiovascular and metabolic diseases, that share the same pathways of accelerated aging. Understanding these mechanisms has helped identify several novel therapeutic targets, and several drugs and dietary interventions are now in development to treat multimorbidity.

    更新日期:2017-09-26
  • Mitochondrial Dysfunction in Lung Pathogenesis
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Claude A. Piantadosi, Hagir B. Suliman

    Remarkable new roles for mitochondria in calcium handling, apoptosis, heme turnover, inflammation, and oxygen and nutrient sensing have been discovered for organelles that were once thought to be simple energy converters. Although deficits in mitochondrial function are often associated with energy failure and apoptosis, working cells maintain a mitochondrial reserve that affords the organelles distinct homeostatic sensing and regulatory abilities in lung cells. As primary intracellular sources of oxidants, mitochondria serve as critical monitors and modulators of vital oxidation-reduction processes, including mitochondrial biogenesis, mitophagy, inflammasome activation, cell proliferation, and prevention of fibrosis. These processes participate in disease pathogenesis in all lung regions mainly when interference with mitochondrial quality control mechanisms impedes their roles in maintenance of lung health. Sharper identification of mitochondrial-driven signaling mechanisms in specific lung cell types will better refine our understanding of respiratory disease pathogenesis and lead to new diagnostic and therapeutic measures to support mitochondrial quality.

    更新日期:2017-09-26
  • Inflammasomes: Key Mediators of Lung Immunity
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Judie A. Howrylak, Kiichi Nakahira

    Inflammasomes are key inflammatory signaling platforms that detect microbial substances, sterile environmental insults, and molecules derived from host cells. Activation of the inflammasome promotes caspase-1-mediated secretion of proinflammatory cytokines interleukin (IL)-1β and IL-18 and pyroptosis. Recent developments in this field demonstrate the crucial role of the inflammasome in a wide range of disease models. Although inflammasomes are a crucial part of host defense mechanisms against pathogens, the exuberant immune response resulting from inflammasome activation also contributes to the development of various diseases. As ongoing studies further elucidate the regulation and function of the inflammasome, more evidence has emerged that the inflammasome appears to play a pivotal role in the development of multiple inflammatory diseases. Here, we discuss recent insights into how inflammasomes are regulated to activate caspase-1 and implicated in human diseases. We also review the contributions of the inflammasome to pulmonary diseases.

    更新日期:2017-09-26
  • Macrophages in Renal Injury and Repair
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Sarah C. Huen, Lloyd G. Cantley

    Acute kidney injury (AKI) is a growing global health concern, yet no treatment is currently available to prevent it or to promote kidney repair after injury. Animal models demonstrate that the macrophage is a major contributor to the inflammatory response to AKI. Emerging data from human biopsies also corroborate the presence of macrophages in AKI and their persistence in progressive chronic kidney disease. Macrophages are phagocytic innate immune cells that are important mediators of tissue homeostasis and host defense. In response to tissue injury, macrophages become activated based on specific signals from the damaged microenvironment. The activation and functional state of the macrophage depends on the stage of tissue injury and repair, reflecting a dynamic and diverse spectrum of macrophage phenotypes. In this review, we highlight our current understanding of the mechanisms by which macrophages contribute to injury and repair after AKI.

    更新日期:2017-09-26
  • Receptor-Mediated Endocytosis in the Proximal Tubule
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Megan L. Eshbach, Ora A. Weisz

    Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular ultrafiltrate to maintain essentially protein-free urine. Compromise of this pathway results in low molecular weight (LMW) proteinuria that can progress to end-stage kidney disease. This review describes our current understanding of the endocytic pathway and the multiligand receptors that mediate LMW protein uptake in PT cells, how these are regulated in response to physiologic cues, and the molecular basis of inherited diseases characterized by LMW proteinuria.

    更新日期:2017-09-26
  • Three Pillars for the Neural Control of Appetite
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Scott M. Sternson, Anne-Kathrin Eiselt

    The neural control of appetite is important for understanding motivated behavior as well as the present rising prevalence of obesity. Over the past several years, new tools for cell type-specific neuron activity monitoring and perturbation have enabled increasingly detailed analyses of the mechanisms underlying appetite-control systems. Three major neural circuits strongly and acutely influence appetite but with notably different characteristics. Although these circuits interact, they have distinct properties and thus appear to contribute to separate but interlinked processes influencing appetite, thereby forming three pillars of appetite control. Here, we summarize some of the key characteristics of appetite circuits that are emerging from recent work and synthesize the findings into a provisional framework that can guide future studies.

    更新日期:2017-09-26
  • Neural Mechanisms for Predicting the Sensory Consequences of Behavior: Insights from Electrosensory Systems
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Nathaniel B. Sawtell

    Perception of the environment requires differentiating between external sensory inputs and those that are self-generated. Some of the clearest insights into the neural mechanisms underlying this process have come from studies of the electrosensory systems of fish. Neurons at the first stage of electrosensory processing generate negative images of the electrosensory consequences of the animal's own behavior. By canceling out the effects of predictable, self-generated inputs, negative images allow for the selective encoding of unpredictable, externally generated stimuli. Combined experimental and theoretical studies of electrosensory systems have led to detailed accounts of how negative images are formed at the level of synaptic plasticity rules, cells, and circuits. Here, I review these accounts and discuss their implications for understanding how predictions of the sensory consequences of behavior may be generated in other sensory structures and the cerebellum.

    更新日期:2017-09-26
  • Trefoil Factor Peptides and Gastrointestinal Function
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Eitaro Aihara, Kristen A. Engevik, Marshall H. Montrose

    Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract.

    更新日期:2017-09-26
  • Tongue and Taste Organ Biology and Function: Homeostasis Maintained by Hedgehog Signaling
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Charlotte M. Mistretta, Archana Kumari

    The tongue is an elaborate complex of heterogeneous tissues with taste organs of diverse embryonic origins. The lingual taste organs are papillae, composed of an epithelium that includes specialized taste buds, the basal lamina, and a lamina propria core with matrix molecules, fibroblasts, nerves, and vessels. Because taste organs are dynamic in cell biology and sensory function, homeostasis requires tight regulation in specific compartments or niches. Recently, the Hedgehog (Hh) pathway has emerged as an essential regulator that maintains lingual taste papillae, taste bud and progenitor cell proliferation and differentiation, and neurophysiological function. Activating or suppressing Hh signaling, with genetic models or pharmacological agents used in cancer treatments, disrupts taste papilla and taste bud integrity and can eliminate responses from taste nerves to chemical stimuli but not to touch or temperature. Understanding Hh regulation of taste organ homeostasis contributes knowledge about the basic biology underlying taste disruptions in patients treated with Hh pathway inhibitors.

    更新日期:2017-09-26
  • The Physiology and Molecular Underpinnings of the Effects of Bariatric Surgery on Obesity and Diabetes
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Simon S. Evers, Darleen A. Sandoval, Randy J. Seeley

    Bariatric surgeries, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, produce significant and durable weight loss in both humans and rodents. Recently, these surgical interventions have also been termed metabolic surgery because they result in profound metabolic improvements that often surpass the expected improvement due to body weight loss alone. In this review we focus on the weight-loss independent effects of bariatric surgery, which encompass energy expenditure and macronutrient preference, the luminal composition of the gut (i.e., the microbiota and bile acids), the transformation of the gastrointestinal lining, increases in postprandial gut hormone secretions, glycemic control, pancreas morphology, and micronutrient and mineral absorption. Taken together, these data point to several important physiological changes that contribute to the profound benefits of these surgical procedures. Identifying the underlying molecular mechanisms for these physiological effects will allow better utilization of these existing procedures to help patients and develop new treatments that harness these surgical effects with less invasive interventions.

    更新日期:2017-09-26
  • The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Huimin Yu, Nesrin M. Hasan, Julie G. In, Mary K. Estes, Olga Kovbasnjuk, Nicholas C. Zachos, Mark Donowitz

    The lack of accessibility to normal and diseased human intestine and the inability to separate the different functional compartments of the intestine even when tissue could be obtained have held back the understanding of human intestinal physiology. Clevers and his associates identified intestinal stem cells and established conditions to grow “mini-intestines” ex vivo in differentiated and undifferentiated conditions. This pioneering work has made a new model of the human intestine available and has begun making contributions to the understanding of human intestinal transport in normal physiologic conditions and the pathophysiology of intestinal diseases. However, this model is reductionist and lacks many of the complexities of normal intestine. Consequently, it is not yet possible to predict how great the advances using this model will be for understanding human physiology and pathophysiology, nor how the model will be modified to include multiple other intestinal cell types and physical forces necessary to more closely approximate normal intestine. This review describes recent studies using mini-intestines, which have readdressed previously established models of normal intestinal transport physiology and newly examined intestinal pathophysiology. The emphasis is on studies with human enteroids grown either as three-dimensional spheroids or two-dimensional monolayers. In addition, comments are provided on mouse studies in cases when human studies have not yet been described.

    更新日期:2017-09-26
  • The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Silvia Ravera, Andrea Reyna-Neyra, Giuseppe Ferrandino, L. Mario Amzel, Nancy Carrasco

    Active iodide (I−) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I− symporter (NIS). In the thyroid, NIS-mediated I− uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. THs are key during embryonic and postembryonic development and critical for cell metabolism at all stages of life. The molecular characterization of NIS in 1996 and the use of radioactive I− isotopes have led to significant advances in the diagnosis and treatment of thyroid cancer and provide the molecular basis for studies aimed at extending the use of radioiodide treatment in extrathyroidal malignancies. This review focuses on the most recent findings on I− homeostasis and I− transport deficiency-causing NIS mutations, as well as current knowledge of the structure/function properties of NIS and NIS regulatory mechanisms. We also discuss employing NIS as a reporter gene using viral vectors and stem cells in imaging, diagnostic, and therapeutic procedures.

    更新日期:2017-09-26
  • Regulation of Mammalian Oocyte Meiosis by Intercellular Communication Within the Ovarian Follicle
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Laurinda A. Jaffe, Jeremy R. Egbert

    Meiotic progression in mammalian preovulatory follicles is controlled by the granulosa cells around the oocyte. Cyclic GMP (cGMP) generated in the granulosa cells diffuses through gap junctions into the oocyte, maintaining meiotic prophase arrest. Luteinizing hormone then acts on receptors in outer granulosa cells to rapidly decrease cGMP. This occurs by two complementary pathways: cGMP production is decreased by dephosphorylation and inactivation of the NPR2 guanylyl cyclase, and cGMP hydrolysis is increased by activation of the PDE5 phosphodiesterase. The cGMP decrease in the granulosa cells results in rapid cGMP diffusion out of the oocyte, initiating meiotic resumption. Additional, more slowly developing mechanisms involving paracrine signaling by extracellular peptides (C-type natriuretic peptide and EGF receptor ligands) maintain the low level of cGMP in the oocyte. These coordinated signaling pathways ensure a fail-safe system to prepare the oocyte for fertilization and reproductive success.

    更新日期:2017-09-26
  • POMC Neurons: From Birth to Death
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Chitoku Toda, Anna Santoro, Jung Dae Kim, Sabrina Diano

    The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.

    更新日期:2017-09-26
  • The Integrative Physiology of Insect Chill Tolerance
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Johannes Overgaard, Heath A. MacMillan

    Cold tolerance is important in defining the distribution of insects. Here, we review the principal physiological mechanisms underlying homeostatic failure during cold exposure in this diverse group of ectotherms. When insects are cooled sufficiently, they suffer an initial loss of neuromuscular function (chill coma) that is caused by decreased membrane potential and reduced excitability of the neuromuscular system. For chill-susceptible insects, chronic or severe chilling causes a disruption of ion and water homeostasis across membranes and epithelia that exacerbate the initial effects of chilling on membrane potential and cellular function, and these perturbations are tightly associated with the development of chill injury and mortality. The adaptation and acclimation responses that allow some insects to tolerate low temperatures are multifactorial and involve several physiological systems and biochemical adjustments. In this review, we outline a physiological model that integrates several of these responses and discuss how they collectively help to preserve cellular, organ, and organismal homeostasis at low temperature.

    更新日期:2017-09-26
  • The Central Control of Energy Expenditure: Exploiting Torpor for Medical Applications
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Matteo Cerri

    Autonomic thermoregulation is a recently acquired function, as it appears for the first time in mammals and provides the brain with the ability to control energy expenditure. The importance of such control can easily be highlighted by the ability of a heterogeneous group of mammals to actively reduce metabolic rate and enter a condition of regulated hypometabolism known as torpor. The central neural circuits of thermoregulatory cold defense have been recently unraveled and could in theory be exploited to reduce energy expenditure in species that do not normally use torpor, inducing a state called synthetic torpor. This approach may represent the first steps toward the development of a technology to induce a safe and reversible state of hypometabolism in humans, unlocking many applications ranging from new medical procedures to deep space travel.

    更新日期:2017-09-26
  • Huxleys’ Missing Filament: Form and Function of Titin in Vertebrate Striated Muscle
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Stan Lindstedt, Kiisa Nishikawa

    Although superthin filaments were inferred from early experiments on muscle, decades passed before their existence was accepted. Phylogenetic analyses suggest that titin, the largest known protein, first appeared in the common ancestor of chordates and nematodes and evolved rapidly via duplication. Twitchin and projectin evolved later by truncation. Sallimus mutants in Drosophila exhibit disrupted sarcomere and chromosome structure, suggesting that giant proteins may have evolved as chromosomal scaffolds that were co-opted for a similar purpose in striated muscles. Though encoded by only one gene, titin comprises hundreds of exons and has the potential for enormous diversity. Shorter isoforms typically confer greater passive stiffness associated with smaller in vivo muscle strains. Recent studies demonstrate unequivocally that titin stiffness increases upon muscle activation, but the mechanisms are only now being uncovered. Although some basic principles have been established, a vast opportunity remains to extend our understanding of titin function in striated muscle.

    更新日期:2017-09-26
  • Anoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Jarred M. Whitlock, H. Criss Hartzell

    Anoctamin (ANO)/TMEM16 proteins exhibit diverse functions in cells throughout the body and are implicated in several human diseases. Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca2+-activated Cl− channels, most ANO paralogs are Ca2+-dependent phospholipid scramblases that serve as channels facilitating the movement (scrambling) of phospholipids between leaflets of the membrane bilayer. Phospholipid scrambling significantly alters the physical properties of the membrane and its landscape and has vast downstream signaling consequences. In particular, phosphatidylserine exposed on the external leaflet of the plasma membrane functions as a ligand for receptors vital for cell–cell communication. A major consequence of Ca2+-dependent scrambling is the release of extracellular vesicles that function as intercellular messengers by delivering signaling proteins and noncoding RNAs to alter target cell function. We discuss the physiological implications of Ca2+-dependent phospholipid scrambling, the extracellular vesicles associated with this activity, and the roles of ANOs in these processes.

    更新日期:2017-09-26
  • A Critical and Comparative Review of Fluorescent Tools for Live-Cell Imaging
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Elizabeth A. Specht, Esther Braselmann, Amy E. Palmer

    Fluorescent tools have revolutionized our ability to probe biological dynamics, particularly at the cellular level. Fluorescent sensors have been developed on several platforms, utilizing either small-molecule dyes or fluorescent proteins, to monitor proteins, RNA, DNA, small molecules, and even cellular properties, such as pH and membrane potential. We briefly summarize the impressive history of tool development for these various applications and then discuss the most recent noteworthy developments in more detail. Particular emphasis is placed on tools suitable for single-cell analysis and especially live-cell imaging applications. Finally, we discuss prominent areas of need in future fluorescent tool development—specifically, advancing our capability to analyze and integrate the plethora of high-content data generated by fluorescence imaging.

    更新日期:2017-09-26
  • Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Keisuke Yanagida, Timothy Hla

    Vertebrates are endowed with a closed circulatory system, the evolution of which required novel structural and regulatory changes. Furthermore, immune cell trafficking paradigms adapted to the barriers imposed by the closed circulatory system. How did such changes occur mechanistically? We propose that spatial compartmentalization of the lipid mediator sphingosine 1-phosphate (S1P) may be one such mechanism. In vertebrates, S1P is spatially compartmentalized in the blood and lymphatic circulation, thus comprising a sharp S1P gradient across the endothelial barrier. Circulatory S1P has critical roles in maturation and homeostasis of the vascular system as well as in immune cell trafficking. Physiological functions of S1P are tightly linked to shear stress, the key biophysical stimulus from blood flow. Thus, circulatory S1P confinement could be a primordial strategy of vertebrates in the development of a closed circulatory system. This review discusses the cellular and molecular basis of the S1P gradients and aims to interpret its physiological significance as a key feature of the closed circulatory system.

    更新日期:2017-09-26
  • The Link Between Angiogenesis and Endothelial Metabolism
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Michael Potente, Peter Carmeliet

    Angiogenesis has traditionally been viewed from the perspective of how endothelial cells (ECs) coordinate migration and proliferation in response to growth factor activation to form new vessel branches. However, ECs must also coordinate their metabolism and adapt metabolic fluxes to the rising energy and biomass demands of branching vessels. Recent studies have highlighted the importance of such metabolic regulation in the endothelium and uncovered core metabolic pathways and mechanisms of regulation that drive the angiogenic process. In this review, we discuss our current understanding of EC metabolism, how it intersects with angiogenic signal transduction, and how alterations in metabolic pathways affect vessel morphogenesis. Understanding EC metabolism promises to reveal new perspectives on disease mechanisms in the vascular system with therapeutic implications for disorders with aberrant vessel growth and function.

    更新日期:2017-09-26
  • Developmental Mechanisms of Aortic Valve Malformation and Disease
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Bingruo Wu, Yidong Wang, Feng Xiao, Jonathan T. Butcher, Katherine E. Yutzey, Bin Zhou

    Normal aortic valves are composed of valve endothelial cells (VECs) and valve interstitial cells (VICs). VICs are the major cell population and have distinct embryonic origins in the endocardium and cardiac neural crest cells. Cell signaling between the VECs and VICs plays critical roles in aortic valve morphogenesis. Disruption of major cell signaling pathways results in aortic valve malformations, including bicuspid aortic valve (BAV). BAV is a common congenital heart valve disease that may lead to calcific aortic valve disease (CAVD), but there is currently no effective medical treatment for this beyond surgical replacement. Mouse and human studies have identified causative gene mutations for BAV and CAVD via disrupted VEC to VIC signaling. Future studies on the developmental signaling mechanisms underlying aortic valve malformations and the pathogenesis of CAVD using genetically modified mouse models and patient-induced pluripotent stem cells may identify new effective therapeutic targets for the disease.

    更新日期:2017-09-26
  • Coronary Artery Development: Progenitor Cells and Differentiation Pathways
    Annu. Rev. Physiol. (IF 11.115) Pub Date : 2017-02-13
    Bikram Sharma, Andrew Chang, Kristy Red-Horse

    Coronary artery disease (CAD) is the number one cause of death worldwide and involves the accumulation of plaques within the artery wall that can occlude blood flow to the heart and cause myocardial infarction. The high mortality associated with CAD makes the development of medical interventions that repair and replace diseased arteries a high priority for the cardiovascular research community. Advancements in arterial regenerative medicine could benefit from a detailed understanding of coronary artery development during embryogenesis and of how these pathways might be reignited during disease. Recent research has advanced our knowledge on how the coronary vasculature is built and revealed unexpected features of progenitor cell deployment that may have implications for organogenesis in general. Here, we highlight these recent findings and discuss how they set the stage to interrogate developmental pathways during injury and disease.

    更新日期:2017-09-26
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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