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The control of breathing during exercise remains the source of considerable debate. Classical schemes of the exercise hyperpnea have incorporated elements of proportional feed-back from chemoreceptor sites (carotid body and brainstem) and feed-forward neurogenic (central command and muscle reflex) control. However, the precise details of the control process are still not fully resolved, reflecting in part technical and interpretational limitations inherent in isolating putative control mechanisms in the intact exercising human and also the challenges presented by the ventilatory and gas-exchange complexities encountered at work rates which engender a metabolic (lactic) acidosis. Although some combination of neurogenic, chemoreflex, and circulatory-coupled processes are likely to contribute to the control, intriguingly, the overall system appears to evidence considerable redundancy. This, coupled with the lack of appreciable steady-state error signals in the mean levels of arterial PCO2, PO2, and pH over a wide range of work rates, has motivated the formulation of innovative control models that reflect not only spatial interactions but also temporal interactions (i.e., short-term and longer-term memory). The challenge remains to discriminate between robust control schemes that (a) integrate such processes within plausible physiological equivalents, and (b) account for both the dynamic and steady-state system response over the entire range of exercise intensities.

Table of Contents: Introduction / Ventilatory Requirements / Ventilatory Responses / Ventilatory Control / Conclusions / References

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Stem cells have great potential in regenerative medicine and tissue injury. Regulation of stem cell homeostasis in a 3D microenvironment is controlled by the niche components that influence stem cell fate, regulation, and function. It is therefore necessary to understand the mechanisms of cellcell interaction, molecular cross talk between stem cells and their extracellular matrix (ECM) environment. The adhesion molecules play a pivotal role in establishing the cellcell contact and subsequent integration with the ECM. This understanding is the basis for establishing design criteria for biomimetic. The integrated approach by biologists, material science engineers, biomedical engineers, and clinicians is the key in the development of tissue engineered constructs for effective translation to clinics.

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The prohormone convertases (PC) 1/3 and 2 are calcium-activated eukaryotic subtilisins with low pH optima which accomplish the limited proteolysis of peptide hormone precursors within neurons and endocrine cells. In this lecture, we review the biochemistry, regulation, and roles of PC1/3 and 2 in disease, with an emphasis on the work published in the last 10 years. In the 20 years since their discovery, a great deal has been learned about their localization and cellular functions. Both PCs share the same four domains: the propeptides perform important roles in controlling activation and targeting; the catalytic domains confer specificity, with PC1/3 possessing a more restricted binding pocket than that of PC2; the P domain is required for expression and contributes to enzymatic properties; and the C-terminal tail assists in proper routing to granules. PC1/3, but not PC2, exists in full-length and C-terminally truncated forms that exhibit different biochemical properties. Both enzymes associate with binding proteins; proSAAS is thought to modulate precursor cleavage by PC1/3, while co-expression of 7B2 is obligatory for the formation of active PC2. Finally, new studies have revealed an increasingly important role for PC1/3 polymorphisms and mutations in glucose homeostasis and obesity.

Table of Contents: General Introduction to the Prohormone Convertases / Prohormone Convertase 1/3 / Prohormone Convertase 2 / Summary and Future Directions / References / Author Biography

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Reactive Oxygen Species and the Cardiovascular System

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Reactive oxygen species (ROS) influence various physiological processes including host defense, hormone biosynthesis, and cellular signaling. Increased ROS production (oxidative stress) is implicated in many diseases of the cardiovascular system, including hypertension, atherosclerosis, cardiac failure, stroke, diabetes, and kidney disease. ROS are produced throughout the cardiovascular system, in the kidney and central and peripheral nervous system. A major source for cardiovascular, renal, and neural ROS is a family of non-phagocytic NAD(P)H oxidases, including the prototypic Nox2 homologue-based NAD(P)H oxidase, as well as other NAD(P)H oxidases, such as Nox1 and Nox4. Other possible sources include mitochondrial electron transport enzymes, xanthine oxidase, cyclooxygenase, lipoxygenase, and uncoupled nitric oxide synthase (NOS). NAD(P)H oxidase-derived ROS is important in regulating endothelial function and vascular tone and oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis and rarefaction, important processes involved in vascular remodeling in cardiovascular disease. These findings have evoked considerable interest because of the possibilities that therapies targeted against non-phagocytic NAD(P)H oxidase to decrease ROS generation and/or strategies to increase nitric oxide (NO) availability and antioxidants may be useful in minimizing vascular injury and thereby prevent or regress target organ damage associated with hypertension and other cardiovascular diseases.

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Neural Control of Gastrointestinal Function

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The gastrointestinal tract is a long, muscular tube responsible for the digestion of food, assimilation of nutrients and elimination of waste. This is achieved by secretion of digestive enzymes and absorption from the intestinal lumen, with different regions playing specific roles in the processing of specific nutrients. These regions come into play sequentially as ingested material is moved along the length of the GI tract by contractions of the muscle layers. In some regions like the oesophagus transit it rapid and measured in seconds while in others like the colon transit is measured in hours and even days, commensurate with the relative slow fermentation that takes place in the large bowel. An hierarchy of controls, neural and endocrine, serve to regulate the various cellular targets that exist in the gut wall. These include muscle cells for contraction and epithelial cells for secretion and absorption. However, there are complex interactions between these digestive mechanisms and other mechanisms that regulate blood flow, immune function, endocrine secretion and food intake. These ensure a fine balance between the ostensibly conflicting tasks of digestion and absorption and protection from potentially harmful ingested materials. They match assimilation of nutrients with hunger and satiety and they ensure that regions of the GI tract that are meters apart work together in a coordinated fashion to match these diverse functions to the digestive needs of the individual. This ebook will provide an overview of the neural mechanisms that control gastrointestinal function.

Table of Contents: Neural Control of Gastrointestinal Function / Cells and Tissues / Enteric Nervous System / From Gut to CNS: Extrinsic Sensory Innervation / Sympathetic Innervation of the Gut / Parasympathetic Innervation of the Gut / Integration of Function / References

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Seizures are more common early in life than in adulthood. Bidirectional interactions between seizures and normal developmental processes define their expression and outcomes. Several developmentally regulated factors control neuronal excitability. GABAA receptors hold a central role as they control neuronal activity in an age-specific manner. Early in development, GABAA receptors have depolarizing effects, which contribute to the increased susceptibility of immature neurons to seizures but they are also essential for normal brain development. During development, there is a gradual shift to the "adult-type" hyperpolarizing GABAA receptor signaling, creating more efficient inhibition. Seizures may disrupt GABAA receptor signaling by changing the expression of their subunits and by changing the direction of GABAA responses, which, in certain situations, may be detrimental for brain development. Furthermore, subcortical nuclei, such as the substantia nigra, control the expression and propagation of seizures in an age- and sex-dependent manner. These endogenous control centers and signaling pathways are further modified by independent genetic epigenetic, biologic, or other factors, which further increase the heterogeneity in presentation of seizures, their treatment, and their comorbidities. Elucidation of these complex interactions and identification of biomarkers guiding therapeutic interventions will be necessary to improve our ability to treat early-life epilepsies.

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The Immune System and the Developing Brain

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The developing brain is exquisitely sensitive to both endogenous and exogenous signals which direct or significantly alter the developmental trajectory of cells, neural circuits, and associated behavioral outcomes for the life of the individual. Contrary to initial dogma that the brain is one of the few organs within the body that is immune-privileged, evidence indicates that the immune system has a critical role in brain function during development as well as during sickness and health in adulthood. Microglia are the primary immune cells within the brain, and they are in constant communication with the peripheral immune system and surrounding cell types within the brain. We describe the important role of the immune system, including microglia, during brain development, and discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, and cognition. Growing evidence indicates that there is a strong link between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. Thus, understanding the role of the immune system and immune activation during the critical period of brain development is a necessary step toward understanding the potential origins of these devastating disorders.

Table of Contents: Introduction / The Immune Response / Brain-Immune Communication / Microglia Are Immune Cells of the Brain / The Functional Role of Microglia and Immune Molecules in Neurodevelopment / Early-Life Programming of Brain and Behavior: A Critical Role for the Immune System / Commonly Used Models of Early Life Immune Activation in the Rodent / Early Life Immune Activation and Cognitive Impairment in Adulthood / Mechanisms Underlying the Enduring Changes in Neuroimmune Function Caused by Early Life Infection / Toll-Like Receptors and Immune Activation During Early Brain Development / Environmental Triggers of TLR Activation: Long-Term Programming of Brain and Behavior / Future Directions to Understanding Immune Function and Brain Development / References

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Development of Brain and Behavior in Birds

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Sex differences in brain and behavior are widespread across vertebrates. Birds exhibit remarkable examples of these types of parallels between structure and function. For example, only male zebra finches sing, and the brain areas and muscles controlling the learning and production of these vocalizations are greatly enhanced in males compared to females. These sex differences are permanently established in development. Some songbirds, unlike zebra finches, change their songs seasonally. In a number of these species, the brain regions exhibit changes in neuron loss and incorporation across these periods. The mechanisms involved in these types of sexual differentiation and adult plasticity are describedthey likely involve both steroid hormones and genetic (protein) factors. The strength of the relationships between morphology and behavior, as well as many other factors, has made birds outstanding models for the investigation of numerous functions. These include the mechanisms regulating vocal learning, auditory perception, neurogenesis, and cell survival. The lessons learned have broad implications for health-related processes and basic biological principles.

Table of Contents: Introduction / Song and Song Learning / Other Social/Reproductive Behaviors / Conclusions and Ideas for Future Directions

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Perinatal Brain Development, Malformation, and Injury

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We provide a broad overview of human brain development with associated malformations and injuries that occur in the period between early embryogenesis and delivery. The aim of this review is to summarize current understanding of the molecular and environmental cues that shape the developing brain. For each developmental stage, we give examples of disorders that arise from genetic and/or environmental insults to illustrate critical points of neurological susceptibility.

Table of Contents: Introduction / Origin of the Central Nervous System: The Neural Tube (3-4 Weeks Gestation) / Patterning of the Neural Tube: A Blueprint for the CNS / Neural Proliferation and Migration (3 Months Gestation Into Postnatal Period) / Organization of Neuronal Circuits and Synaptogenesis (5 Months Gestation-Postnatal Years) / Gliogenesis and Myelination (5-Month Childhood) / Developmental Brain Injury: Before, During, and After Birth / Conclusion / References / Author Biographies

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Motor Function of the Pharynx, Esophagus, and its Sphincters

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Deglutition or a swallow begins as a voluntary act in the oral cavity but proceeds autonomously in the pharynx and esophagus. Bilateral sequenced activation and inhibition of more than 25 pairs of muscles of mouth, pharynx, larynx, and esophagus is required during a swallow. A single swallow elicits peristalsis in the pharynx and esophagus along with relaxation of upper and lower esophageal sphincters. Multiple swallows, at closely spaced time intervals, demonstrate deglutitive inhibition; sphincters remain relaxed during the entire period, but only the last swallow elicits peristalsis. Laryngeal inlet closure or airway protection is very important during swallow. Upper part of the esophagus that includes upper esophageal sphincter is composed of skeletal muscles, middle esophagus is composed of a mixture of skeletal and smooth muscles, and lower esophagus, including lower esophageal sphincter, is composed of smooth muscles. Peristalsis progresses in seamless fashion, despite separate control mechanism, from the skeletal to smooth muscle esophagus. The esophagus's circular and longitudinal muscle layers contract synchronously during peristalsis. Sphincters maintain continuous tone; neuromuscular mechanisms for tonic closure in the upper and lower esophageal sphincters are different. Lower esophageal sphincter transient relaxation, belching mechanism, regurgitation, vomiting, and reflux are mediated via the brain stem.

Table of Contents: Introduction / Central Program Generator and Brain Stem / Pharynx-Anatomy, Neural Innervation, and Motor Pattern / Upper Esophageal Sphincter / Neuromuscular Anatomy of Esophagus and Lower Esophageal Sphincter / Extrinsic Innervation: Parasympathetic and Sympathetic / Interstitial Cells of Cajal / Recording Techniques / Motor Patterns of the Esophagus-Aboral and Oral Transport / Deglutitive Inhibition and Muscle Refractoriness / Peristalsis in the Circular and Longitudinal Muscles of the Esophagus / Neural and Myogenic Mechanism of Peristalsis / Central Mechanism of Peristalsis-Cortical and Brain Stem Control / Peripheral Mechanisms of Peristalsis / Central Versus Peripheral Mechanism of Deglutitive Inhibition / Neural Control of Longitudinal Muscle Contraction / Modulation of Primary and Secondary Peristalsis / Neural Control of Lower Esophageal Sphincter and Crural Diaphragm / Lower Esophageal Sphincter / Swallow-Induced LES Relaxation / Crural Diaphragm Contribution to EGJ and Neural Control / Transient LES Relaxation and Pharmacological Inhibition / Compliance of the EGJ / References

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EDHF-Mediated Responses "The Classical Pathway"

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The endothelium controls vascular tone by releasing various vasoactive substances. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca concentration of the endothelial cells followed by the opening of Ca-activated K channels of small and intermediate conductances (SKCa and IKCa). These channels show a distinct subcellular distribution, suggesting that their activation could be elicited by distinct stimuli. Following KCa activation, the endothelial hyperpolarization can be conducted to the underlying smooth muscle cells by electrical coupling through myo-endothelial gap junctions. In addition, the potassium efflux can lead to the accumulation of potassium ions in the intercellular space and the subsequent activation of smooth muscle Kir2.1 and/or Na/K-ATPase. The hyperpolarization of the smooth muscle cells produces vascular relaxation, predominantly by closing voltage-gated calcium channels, and vasodilatation. EDHFmediated responses are altered in various pathologies or, conversely, act as a compensating mechanism when other endothelial pathways are impaired. A better characterization of EDHF-mediated responses should allow determining whether or not new drugable targets can be identified within this endothelial pathway for the treatment of cardiovascular diseases.

Table of Contents: Endothelium-Dependent Hyperpolarizations: The Classical "EDHF" Pathway / Conclusion / References

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Minute-to-minute behavior of the alimentary tract reflects the integrated functioning of the gut's musculature, secretory glands and bloodlymphatic vasculature. Activity of the three effector systems to generate functionally effective patterns of behavior, which are adaptive for differing digestive states, is organized and coordinated by the enteric nervous system (i.e., the brain-in-the-gut). The heuristic model for the enteric nervous system (ENS) is the same as for all integrative nervous systems, whether in vertebrate or invertebrate animals. Like other integrative nervous systems, such as the spinal cord and brain stem, the ENS functions with sensory neurons, interneurons and motor neurons. That the gut does not work without the ENS can be made as an absolute statement. This is apparent in its absence in terminal regions of the large intestine in Hirschsprung's disease in humans and animals where it is reflected by dysfunctional motility, failure of defecation and proximal fecal compaction within a proximal megacolon. Autoimmune ablation of the ENS in the lower esophageal sphincter underlies the pathophysiology of achalasia. Furthermore, neuropathic degeneration of ENS neurons in irritable bowel syndrome, other functional gastrointestinal disorders, intestinal pseudoobstruction, Chagas disease, paraneoplastic syndrome and enteric ganglionitis, underlies the morbidity associated with these disorders. The impact of these clinical disorders on quality of life and cost of health care is a reminder of the importance of the ENS for a normally functioning gut. Moreover, our incomplete understanding of the pathobiology of these disorders highlights a need for research directed to expansion of current knowledge of the neurobiology of the ENS at all levels of organization from the cellular biology of individual neurons to the biophysics of integrated networks to whole organ behavior. Investigation of the normal and disordered ENS and its interactions with the central nervous system is a branch of neurogastroenterology. Neurogastroenterology is a scientific and clinical subspecialty of gastroenterology that deals with the neural mechanisms that influence function of the digestive tract and that underlie projection of conscious sensations to the gut.

Table of Contents: Introduction / Historical Perspective / Heuistic Model / Microanatomy / Sensory Neurophysiology / Interneurons / Enteric Motor Neurons / Disinhibitory Motor Disorders / Neuronal Electrical Behavior / Synaptic Transmission / Organ Level Integration / Gastric Motor Integration / Integrated Control of the Small and Large Intestines / Plasticity in the ENS / Small Intestine Motility / Defecation / References

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In this lecture, we will briefly review the principles of physics, central metabolism, and cell biology that make health possible. This exercise is appropriate for those of us who have set before ourselves the problem of understanding and preserving life processes, because it is through the medium of a cell that energy creates life. We are aware that life processes require a complex set of biochemical reactions. But that is not enough. Not only are complex reactions necessary, but superimposed on this essential requirement is the necessity to build and maintain a dynamic cellular structure. Chemical energy builds cells. In this lecture, we will see how cells extract energy from the entropic dissolution of the universe, how the extracted energy is used to build cell structure, and how cell structure determines cell function.

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Angiogenesis is the growth of blood vessels from the existing vasculature. The field of angiogenesis has grown enormously in the past 30 years, with only 40 papers published in 1980 and nearly 6000 in 2010. Why has there been this explosive growth in angiogenesis research? Angiogenic therapies provide a potential to conquer cancer, heart diseases, and more than 70 of lifes most threatening medical conditions. The lives of at least 1 billion people worldwide could be improved with angiogenic therapy, according to the Angiogenesis Foundation. In this little book, we provide a simple approach to understand the essential elements of the angiogenic process, we critique the most powerful angiogenesis assays that are used to discover proangiogenic and antiangiogenic substances, and we provide an in-depth physiological perspective on how angiogenesis is regulated in normal, healthy tissues of the human body. All tissues of the body require a continuous supply of oxygen to burn metabolic substrates that are needed for energy. Oxygen is conducted to these tissues by blood capillaries: more capillaries can improve tissue oxygenation and thus enhance energy production; fewer capillaries can lead to hypoxia and even anoxia in the tissues. This means that angiogenic therapies designed to control the growth and regression of blood capillaries can be used to improve the survival of poorly perfused tissues that are essential to the body (heart, brain, skeletal muscle, etc.) and to rid the body of unwanted tissues (tumors).

Table of Contents: Overview of Angiogenesis / Angiogenesis Assays / Regulation: Metabolic Factors / Regulation: Mechanical Factors / Glossary / References / Author Biographies

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Heme oxygenases (HOs) are the enzymes responsible for the breakdown of heme and the generation of biliverdin/bilirubin and carbon monoxide (CO). The kidney is a complex organ consisting of many different cell types all working together for the single purpose of filtering the blood to eliminate waste products and conserving ions, minerals, and water necessary for life. HO enzymes and their products play a critical role in the normal function of the kidney as well as protecting the kidney from various insults including ischemia and exposure to nephrotoxins. For example, the HO metabolite, bilirubin, is a potent antioxidant which can limit damage to renal tubular epithelial cells following exposure to nephrotoxins associated with chemotherapy or traumatic injury. Another HO metabolite, CO, is an important vasodilator of renal blood vessels and helps protect against severe decreases in renal blood flow in conditions as diverse as exposure to radiocontrast agents and in hypertension-induced kidney disease. HO and its metabolites also play an important role in the survival of kidney cells after acute and chronic injuries by regulating important cell growth and programmed cell death pathways. The intent of this volume is to highlight the important role that HO enzymes and their related metabolites, bilirubin and CO, play in the regulation of renal function and in the response of the kidney to both acute and chronic pathologies.

Table of Contents: Introduction to the HO System / HO and Renal Vascular Function / HO and Renal Tubule Function / HO and Acute Kidney Injury / HO and Chronic Kidney Injury / Future of Renal HO Research / References

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The human gut is the natural habitat for a diverse and dynamic microbial ecosystem having an important impact on health and disease. Bacteria have lived in and on animal hosts since multicellular life evolved about 1 billion years ago. Hosts provide habitat and nutrition to the microbial communities and derive many benefits from their guests that contribute with metabolic (recovery of energy and nutrients), defensive (barrier effect against invaders) and trophic (immune regulation, neuro-endocrine development) functions. Several disease states or disorders have been associated with changes in the composition or function of the enteric microbiota, including inflammatory bowel diseases, obesity and the metabolic syndrome. Probiotics and prebiotics can be used to improve symbiosis between enteric microbiota and host, or correct states of dysbiosis.

Table of Contents: Microbial Communities / Host-Microbe Interactions in the Gut / Composition of the Human Enteric Microbiota / Acquisition of the Enteric Microbiota / Dysfunction of the Enteric Microbiota / Therapeutic Manipulation of the Enteric Microbiota / References / Author Biography

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The aim of this treatise is to summarize the current understanding of the mechanisms for blood flow control to skeletal muscle under resting conditions, how perfusion is elevated (exercise hyperemia) to meet the increased demand for oxygen and other substrates during exercise, mechanisms underlying the beneficial effects of regular physical activity on cardiovascular health, the regulation of transcapillary fluid filtration and protein flux across the microvascular exchange vessels, and the role of changes in the skeletal muscle circulation in pathologic states. Skeletal muscle is unique among organs in that its blood flow can change over a remarkably large range. Compared to blood flow at rest, muscle blood flow can increase by more than 20-fold on average during intense exercise, while perfusion of certain individual white muscles or portions of those muscles can increase by as much as 80-fold. This is compared to maximal increases of 4- to 6-fold in the coronary circulation during exercise. These increases in muscle perfusion are required to meet the enormous demands for oxygen and nutrients by the active muscles. Because of its large mass and the fact that skeletal muscles receive 25% of the cardiac output at rest, sympathetically mediated vasoconstriction in vessels supplying this tissue allows central hemodynamic variables (e.g., blood pressure) to be spared during stresses such as hypovolemic shock. Sympathetic vasoconstriction in skeletal muscle in such pathologic conditions also effectively shunts blood flow away from muscles to tissues that are more sensitive to reductions in their blood supply that might otherwise occur. Again, because of its large mass and percentage of cardiac output directed to skeletal muscle, alterations in blood vessel structure and function with chronic disease (e.g., hypertension) contribute significantly to the pathology of such disorders. Alterations in skeletal muscle vascular resistance and/or in the exchange properties of this vascular bed also modify transcapillary fluid filtration and solute movement across the microvascular barrier to influence muscle function and contribute to disease pathology. Finally, it is clear that exercise training induces an adaptive transformation to a protected phenotype in the vasculature supplying skeletal muscle and other tissues to promote overall cardiovascular health.

Table of Contents: Introduction / Anatomy of Skeletal Muscle and Its Vascular Supply / Regulation of Vascular Tone in Skeletal Muscle / Exercise Hyperemia and Regulation of Tissue Oxygenation During Muscular Activity / Microvascular Fluid and Solute Exchange in Skeletal Muscle / Skeletal Muscle Circulation in Aging and Disease States: Protective Effects of Exercise / References

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The discovery of a potent vasoconstrictor, endothelin (ET)-1, derived from vascular endothelial cells was among a variety of key lines of investigation that helped to fuel a major explosion of studies related to endothelial cell biology. This was particularly evident within the pharmaceutical industry where receptor antagonists were quickly developed and are now on the market for treatment of pulmonary hypertension and in development for other diseases such as diabetic nephropathy and cancer. Importantly, we know that the kidney contains the highest level of ET-1 production and receptor expression in the body where it has been demonstrated to function as a pro-natriuretic autocrine and paracrine factor that is activated in conditions of high salt intake. This eBook provides a review of the various mechanisms whereby ET-1 has been shown to function within the kidney through a wide range of actions that include direct effects on tubular transport, intrarenal hemodynamics, as well as neural and endocrine functions. Much has yet to be discerned, but it is clear that the ET system is a major physiological regulator of fluid-electrolyte balance and blood pressure through these renal actions.

Table of Contents: Discovery of Endothelin / Basic Biology of the Endothelin System / Renal Localization / Renal Hemodynamics / Renal Tubular Actions of Endothelin / Endothelin in Neural Modulation of Renal Function / Physiological Role of Endothelin / Endothelin in Renal Pathology / References / Author Biographies

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Contractility describes the relative ability of the heart to eject a stroke volume (SV) at a given prevailing afterload (arterial pressure) and preload (end-diastolic volume; EDV). Various measures of contractility are related to the fraction as the SV/EDV or the ejection fraction, and the dynamics of ejection as determined from maximum pressure rise in the ventricles or arteries or from aortic flow velocities determined by echocardiography. At the cellular level, the ultimate determinant of contractility is the relative tension generation and shortening capability of the molecular motors (myosin cross-bridges) of the sarcomeres as determined by the rates and extent of Ca activation, the turnover kinetics of the cross-bridges, and the relative Ca responsiveness of the sarcomeres. Engagement of the regulatory signaling cascades controlling contractility occurs with occupancy and signal transduction by receptors for neurohumors of the autonomic nervous system as well as growth and stress signaling pathways. Contractility is also determined by the prevailing conditions of pH, temperature, and redox state. Short-term control of contractility is fully expressed during exercise. In long-term responses to stresses on the heart, contractility is modified by cellular remodeling and altered signaling that may compensate for a time but which ultimately may fail, leading to disorders.

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Regulation of Vascular Smooth Muscle Function

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Vascular smooth muscle (VSM) constitutes most of the tunica media in blood vessels and plays an important role in the control of vascular tone. Ca2+ is a major regulator of VSM contraction and is strictly regulated by an intricate system of Ca2+ mobilization and Ca2+ homeostatic mechanisms. The interaction of a physiological agonist with its plasma membrane receptor stimulates the hydrolysis of membrane phospholipids and increases the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates Ca2+ release from the intracellular stores in the sarcoplasmic reticulum. Agonists also stimulate Ca2+ influx from the extracellular space via voltage-gated, receptor-operated, and store-operated channels. Ca2+ homeostatic mechanisms tend to decrease the intracellular free Ca2+ concentration ([Ca2+]i) by activating Ca2+ extrusion via the plasmalemmal Ca2+ pump and the Na+/Ca2+ exchanger and the uptake of excess Ca2+ by the sarcoplasmic reticulum and possibly the mitochondria. A threshold increase in [Ca2+]i activates Ca2+-dependent myosin light chain (MLC) phosphorylation, stimulates actinmyosin interaction, and initiates VSM contraction. The agonist-induced maintained increase in DAG also activates specific protein kinase C (PKC) isoforms, which in turn cause phosphorylation of cytoplasmic substrates that increase the contractile myofilaments force sensitivity to Ca2+ and thereby enhance VSM contraction. Agonists could also activate Rho kinase (ROCK), leading to inhibition of MLC phosphatase and further enhancement of the myofilaments force sensitivity to Ca2+. The combined increases in [Ca2+]i, PKC and ROCK activity cause significant vasoconstriction and could also stimulate VSM hypertrophy and hyperplasia. The protracted and progressive activation of these processes could lead to pathological vascular remodeling and vascular disease.