David P. White, MD

• Harvard Medical School and Brigham and Women?
• Hospital, Boston, MA, USA

Fluid shear stress induces differentiation of circulating phenotype endothelial progenitor cells gastritis icd 10 purchase 250mg biaxin with mastercard. Involvement of E-selectin in recruitment of endothelial progenitor cells and angiogenesis in ischemic muscle gastritis symptoms weakness order biaxin 500mg with amex. Maintenance and repair of the lung endothelium does not involve contributions from marrow-derived endothelial precursor cells gastritis in cats purchase biaxin pills in toronto. The effect of supplementation of grape seed proanthocyanidin extract on vascular dysfunction in experimental diabetes gastritis symptoms upper right quadrant pain buy 500mg biaxin. Circulating endothelial progenitor cells and large artery structure and function in young subjects with uncomplicated type 1 diabetes gastritis quick cure order biaxin on line amex. Angiotensin-(1-7) administration benefits cardiac gastritis remedy food discount biaxin 500mg mastercard, renal and progenitor cell function in db/ db mice. Severe type 2 diabetes induces reversible modifications of endothelial progenitor cells which are ameliorate by glycemic control. Nifedipine improves the migratory ability of circulating endothelial progenitor cells depending on manganese superoxide dismutase upregulation. Endothelial progenitor cell mobilization and increased intravascular nitric oxide in patients undergoing cardiac rehabilitation. Increasing doses of simvastatin versus combined ezetimibe/simvastatin: Effect on circulating endothelial progenitor cells. High-density lipoprotein exerts vasculoprotection via endothelial progenitor cells. The effect of type-2-diabetes-related vascular endothelial dysfunction on skin physiology and activities of daily living. Effect of normalization of fasting glucose by intensified insulin therapy and influence of enos polymorphisms on the incidence of restenosis after peripheral angioplasty in patients with type 2 diabetes: A randomized, open-label clinical trial. Plasticity of human adipose lineage cells toward endothelial cells: Physiological and therapeutic perspectives. Comparison of the effects of ramipril versus telmisartan on high-sensitivity C-reactive protein and endothelial progenitor cells after acute coronary syndrome. Allogeneic mesenchymal stem cells restore endothelial function in heart failure by stimulating endothelial progenitor cells. Proteomics identifies thymidine phosphorylase as a key regulator of the angiogenic potential of colonyforming units and endothelial progenitor cell cultures. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Functional disruption of alpha4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization. Period2 deficiency blunts hypoxia-induced mobilization and function of endothelial progenitor cells. Sonic hedgehog improves ischemia-induced neovascularization by enhancing endothelial progenitor cell function in type 1 diabetes. Combined strategy of mesenchymal stem cell injection with vascular endothelial growth factor gene therapy for the treatment of diabetes-associated erectile dysfunction. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Endothelial Progenitor Cells: Properties, Function, and Response to Toxicological Stimuli 177 Redondo, S. Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: Involvement of peroxisome proliferator-activated receptor-gamma and transforming growth factor-beta1. Effect of body mass index on early outcomes in patients undergoing coronary artery bypass surgery. Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors. Exercise acutely increases circulating endothelial progenitor cells and monocyte-/ macrophage-derived angiogenic cells. Progenitor cells are mobilized by acute psychological stress but not betaadrenergic receptor agonist infusion. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: A systematic review of cohort studies. Impact of age and gender interaction on circulating endothelial progenitor cells in healthy subjects. Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia. Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells. Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: Focus on oxidative stress and endothelial progenitor cells. Diabetes alters subsets of endothelial progenitor cells that reside in blood, bone marrow, and spleen. Bone marrow chimerism prevents atherosclerosis in arterial walls of mice deficient in apolipoprotein E. Effects of exercise and ischemia on mobilization and functional activation of blood-derived progenitor cells in patients with ischemic syndromes: Results of 3 randomized studies. Bone marrow-derived endothelial progenitor cells confer renal protection in a murine chronic renal failure model. Effects of exercise training on endothelial progenitor cells in patients with chronic heart failure. Effect of intensive lipid-lowering therapy on telomere erosion in endothelial progenitor cells obtained from patients with coronary artery disease. Maternal circulating endothelial progenitor cells in normal singleton and twin pregnancy. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: Proof of concept for the clinical importance of endogenous vascular repair. Leptin enhances the recruitment of endothelial progenitor cells into neointimal lesions after vascular injury by promoting integrin-mediated adhesion. Vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy. Estradiol-mediated endothelial nitric oxide synthase association with heat shock protein 90 requires adenosine monophosphate-dependent protein kinase. Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy. Nitric oxide cytoskeletal-induced alterations reverse the endothelial progenitor cell migratory defect associated with diabetes. Preadipocytes in the human subcutaneous adipose tissue display distinct features from the adult mesenchymal and hematopoietic stem cells. Effect of acute exercise on endothelial progenitor cells in patients with peripheral arterial disease. Endothelial progenitor cells in subclinical hypothyroidism: the effect of thyroid hormone replacement therapy. Dynamic regulation of estrogen receptor-alpha isoform expression in the mouse fallopian tube: Mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors. Circulating endothelial progenitor cells, endothelial function, carotid intima-media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria. Transplantation of bone marrow-derived mononuclear cells in ischemic apolipoprotein Eknockout mice accelerates atherosclerosis without altering plaque composition. Increased levels of circulating endothelial progenitor cells in patients with ischaemic stroke treated with statins during acute phase. Exercise training improves in vivo endothelial repair capacity of early endothelial progenitor cells in subjects with metabolic syndrome. Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: Restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Pioglitazone improves in vitro viability and function of endothelial progenitor cells from individuals with impaired glucose tolerance. Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. Synergistic effects of telmisartan and simvastatin on endothelial progenitor cells. An ex vivo angiogenesis assay utilizing commercial porcine carotid artery: Modification of the rat aortic ring assay. Human adipose-derived stem cells enhance the angiogenic potential of endothelial progenitor cells, but not of human umbilical vein endothelial cells. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Decrease and senescence of endothelial progenitor cells in patients with preeclampsia. Nicotine enlivenment of blood flow recovery following endothelial progenitor cell transplantation into ischemic hindlimb. Shift work is a risk factor for increased blood pressure in Japanese men: A 14-year historical cohort study. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Blockade of advanced glycation end-product formation restores ischemiainduced angiogenesis in diabetic mice. Impairment in ischemia-induced neovascularization in diabetes: Bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. Effects of losartan on the mobilization of endothelial progenitor cells and improvement of endothelial function. Endothelial Progenitor Cells: Properties, Function, and Response to Toxicological Stimuli 179 Tepper, O. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Late outgrowth endothelial progenitor cells in patients with age-related macular degeneration. A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Strenuous exercise increases late outgrowth endothelial cells in healthy subjects. Bone marrow molecular alterations after myocardial infarction: Impact on endothelial progenitor cells. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormonemediated increase of insulin-like growth-factor-1. Impairment of endothelial progenitor cell function and vascularization capacity by aldosterone in mice and humans. Oxidized low-density lipoprotein induces apoptosis in endothelial progenitor cells by inactivating the phosphoinositide 3-kinase/Akt pathway. N-3 polyunsaturated fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity. Effects of rosuvastatin and allopurinol on circulating endothelial progenitor cells in patients with congestive heart failure: the impact of inflammatory process and oxidative stress. Probucol and antioxidant vitamins rescue ischemia-induced neovascularization in mice exposed to cigarette smoke: Potential role of endothelial progenitor cells. Fish oil-enriched diet protects against ischemia by improving angiogenesis, endothelial progenitor cell function and postnatal neovascularization. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Aktendothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. Human endothelial progenitors constitute targets for environmental atherogenic polycyclic aromatic hydrocarbons. Hypercholesterolemia reduces collateral artery growth more dominantly than hyperglycemia or insulin resistance in mice. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Low concentration of ethanol favors progenitor cell differentiation and neovascularization in high-fat diet-fed mice model. C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: Further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Exercise on progenitor cells in healthy subjects and patients with type 1 diabetes. Statin therapy accelerates reendothelialization: A novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Increasing physical education in high school students: Effects on concentration of circulating endothelial progenitor cells.

Diseases

• Deafness vitiligo achalasia
• Glyceraldehyde-3-phosphate dehydrogenase deficiency
• Ichthyosis linearis circumflexa
• Pfeiffer Palm Teller syndrome
• Charcot Marie Tooth disease type 1A
• Hyperparathyroidism

Various collection and preparation methods have been described and are generally of comparable quality if appropriately executed (Reagan et al gastritis symptom of celiac disease biaxin 500mg on-line. As with histologic sections gastritis diet zen biaxin 500 mg line, a number of special stains may be used to identify specific constituents gastritis symptoms difficulty swallowing purchase on line biaxin. Bone marrow smear evaluation generally consists of a quantitative evaluation of cell lineages and maturation sequences gastritis diet ������� 250mg biaxin overnight delivery, in addition to assessment of cell morphology gastritis symptoms burning sensation effective 250 mg biaxin. If more detailed assessment of the maturation sequence is required gastritis diet 500 buy discount biaxin 500 mg online, myeloid and erythroid cells can be classified into mitotic and maturing pools, or a complete differential count including all developmental stages of each lineage can be performed. It is important that these ratios and differential counts be done in areas of the slide where individual cells can be identified but where peripheral blood is excluded. Visual assessment of the relative proportion of myeloid and erythroid cells and their maturation sequences, in addition to cell morphology, may also provide useful information in the absence of performing an M:E ratio or complete differential count. The combination of bone marrow cellularity and M:E ratio (or relative proportions) provides information about whether myeloid and erythroid cell lineages are decreased, normal, or increased in number and help to characterize changes in peripheral blood cell numbers. Morphologic changes in these lineages may also suggest abnormal division or maturation or other pathophysiologic processes. Other cell types, including megakaryocytes, lymphocytes, plasma cells, macrophages, and mast cells, are not included in the differential count but should be assessed for abnormal number or morphology. Cytochemical stains applied to cytologic specimens may also be useful in some circumstances to aid in the identification of specific cell lineages, but are infrequently used in toxicology studies. These stains include Sudan Black B, myeloperoxidase, and chloroacetate esterase as neutrophil markers; nonspecific esterases (a-naphthyl acetate esterase and a-naphthyl butyrate esterase) as monocyte/macrophage markers; and toluidine blue to identify basophils and mast cells. Cellularity and staining quality are adequate to perform enumeration and morphologic characterization of hematopoietic cells. Immunocytochemical techniques, using direct or indirect immunofluorescent techniques, can also be applied to films of aspirated marrow or cytocentrifuged preparations of washed cells. Many polyclonal and monoclonal antibodies have been developed to identify a wide variety of both cytoplasmic and surface determinants on hematopoietic cells. Similarly, many immunohistochemical reagents can be applied to paraffin-embedded sections of decalcified marrow. Plastic embedding is in most cases not suitable for immunological techniques (Bain et al. With the ever-increasing identification of membrane determinants unique to primitive stem cells and progenitor cells, flow cytometric analysis can be utilized to quantify, enrich, or purify hematopoietic cells. In particular, flow cytometry methods have been evaluated for bone marrow differential counts and M:E ratios in multiple laboratory animal species (Martin et al. Bone marrow differential counts using a flow cytometry-based automated hematology instrument have also been evaluated for rats (Criswell et al. Although the information provided by flow cytometric methods is similar to that provided by bone marrow cytology, morphologic evaluation is not possible and therefore concurrent evaluation of cytologic bone marrow preparations should be considered in order to assess cell morphology. Stem cells and progenitor cells from all hematopoietic lineages can be quantified and preserved in semisolid short-term culture systems using agar or methylcellulose. In addition, these systems can be used to study regulatory factors and their interactions. As stem cells and progenitor cells bear no distinguishing morphologic features, all resembling lymphoid cells, these systems have been critical to understanding events in hematopoiesis that occur at levels preceding development of recognizable precursors in marrow. However, growth of hematopoietic cells under these conditions is very temporary (Metcalf, 1993). It is interesting to note that two-thirds of the cells in these cultures are stromal cells, including fibroblasts, endothelial cells, adipocytes, and accessory cells of lymphohematopoietic origin. Hematopoiesis can be maintained for weeks, and self-renewing pluripotent stem cells are maintained and permitted to differentiate. The hematopoietic microenvironment: the functional and structural basis of blood cell development (1st edn. Differentiation of human basophils: an overview of recent advances and pending questions. Interaction of human bone marrow fibroblasts with megakaryocytes: role of the c-kit ligand. The transmural passage of blood cells into myeloid sinusoids and the entry of platelets into the sinusoidal circulation: a scanning electron microscopic investigation. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. Ultrastructural studies of transmural migration of blood cells in the bone marrow of rats, mice and guinea pigs. Hamonectin: a bone marrow adhesion protein specific for cells of granulocytic lineage. Bone marrow stroma in humans: anti-nerve growth factor receptor antibodies selectively stain reticular cells in vivo and in vitro. The hematopoietic microenvironment: the functional and structural basis of blood cell development (pp. Comparison of flow cytometric and manual bone marrow differentials in Wistar rats. Surface membrane-associated regulation of cell assembly, differentiation, and growth. Changes in the random distribution of sialic acid at the surface of the myeloid sinusoidal endothelium resulting from the presence of diaphragmed fenestrae. Expression of platelet glycoprotein Ib by cultured human megakaryocytes: ultrastructural localization and biosynthesis. Characterization of a bipotent erythro-megakaryocytic progenitor in human bone marrow. Interpreting stress responses during routine toxicity studies: a review of the biology, impact, and assessment. Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway. Short-term injection of antiapoptotic cytokine combinations soon after lethal g-irradiation promotes survival. Stathmin prevents the transition from a normal to an endomitotic cell cycle during megakaryocytic differentiation. Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hematopoietic progenitors. Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and y-irradiated mice. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombopoiesis. Promotion of megakaryocyte progenitor expansion and differentiation by c-Mpl ligand thrombopoietin. Plasma levels and production of soluble stem cell factor by marrow stromal cells in patients with aplastic anemia. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibers. Peritubular cells are the site of erythropoietin protein synthesis in the murine hypoxic kidney. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells. Parasinusoidal location of megakaryocytes in marrow: a determinant of platelet release. Thrombospondin functions as a cytoadhesion molecule for human hematopoietic progenitor cells. The hematopoietic microenvironment: the functional and structural basis of blood cell development. Immature megakaryocytes in the mouse: in vitro relationship to megakaryocyte progenitor cells and mature megakaryocytes. Stem cell factor induction of in vitro murine hematopoietic colony formation by "subliminal" cytokine combinations: the role of "anchor factors". The kinetic status of hematopoietic stem cells subpopulations underlies a differential expression of genes involved in self-renewal, commitment, and engraftment. Multipotential hematopoietic blast colony-forming cells exhibit delays in self-generation and lineage commitment. Distinct roles of erythropoietin, insulin-like growth factor I, and stem cell factor in the development of erythroid progenitor cells. Bone marrow stromal cells produce thrombopoietin and stimulate megakaryocyte growth and maturation but suppress proplatelet formation. The microvasculature of the human bone marrow correlated with the distribution of hematopoietic cells. A stochastic model of self-renewal and commitment to differentiation of the primitive hemopoietic stem cells in culture. Interleukin-6 and its receptor are expressed by human megakaryocytes: in vitro effects on proliferation and endoreduplication. Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes. A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking. Granulocyte colony-stimulating factor enhances the phagocytic and bactericidal activity of normal and defective human neutrophils. Purification of human burst-forming units-erythroid and demonstration of the evolution of erythropoietin receptors. Alphasmooth muscle actin is expressed in a subset of bone marrow stromal cells in normal and pathological conditions. Characterization of the megakaryocyte demarcation system and its role in thrombopoiesis. Erythropoietin can induce the expression of bcl-xl through stat 5 in erythropoietin-dependent progenitor cell lines. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. RhoA is essential for maintaining normal megakaryocyte ploidy and platelet generation. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Arterial structure of the bone marrow in rabbit with pecial reference to thin-walled arteries. Marrow adipose cells: histochemical identification of labile and stable compartments. Fusion-fission reorganization of membrane: a developing membrane model for thrombocytogenesis in megakaryocytes. Absence of tight junction in endothelium of marrow sinuses: possible significance for marrow cells egress. Two monoclonal antiplatelet antibodies as markers of human megakaryocyte maturation: immunofluorescent staining and platelet peroxidase detection in megakaryocyte colonies and in in vivo cells from normal and leukemic patients. The hematopoietic microenvironment of the bone marrow: an ultrastructural study of the stroma in rats. Barrier cells: stromal regulation of hematopoiesis and blood cell release in normal and stressed murine bone marrow. Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the "neuro-reticular complex". Migration of erythroblastic islands toward the sinusoid as erythroid maturation proceeds in rat bone marrow. Megakaryocytopoiesis: incorporation of tritiated thymidine by small acetylcholinesterase-positive cells in murine bone marrow during antibodyinduced thrombocytopenia. Molecular basis of the recognition of intravenously transplanted hematopoietic cells by the bone marrow.

Clinical studies have shown that allopurinol treatment improves endothelial dysfunction in patients with cardiovascular disease gastritis diet vegetable recipes order biaxin once a day, including coronary artery disease (Doehner et al gastritis ruq pain purchase cheapest biaxin and biaxin. A normally functioning endothelium is responsible for maintaining appropriate vascular blood flow gastritis diet ������ biaxin 500mg lowest price. Importantly gastritis diet ����� purchase discount biaxin on line, the degree of endothelial dysfunction in individuals with cardiovascular disease can be used as a prognostic indicator for clinical outcomes lymphocytic gastritis symptoms treatment discount biaxin 500 mg on line. The panels show in situ localization of superoxide production (indicated by red fluorescence) in transverse sections (10 mm) of rabbit carotid artery gastritis diet ������ generic 250mg biaxin. The dihydroethidium fluorescence is predominantly found in the endothelial layer and the adventitia in the vehicle-collared artery section (A), and is suppressed by the local in vivo treatment with apocynin (C). This is an update of E Wilson, Mechanical Forces and Vascular Injury, Comprehensive Toxicology, Second Edition, edited by Charlene A. This article will introduce the various types of mechanical forces to which the vascular wall is exposed, the current thoughts on how cells sense and respond to changes in mechanical forces, and details of how the altered mechanical environments contribute to vascular injury and development of disease. Additionally, we will look at the data linking of genetic and environmentally-induced changes in the vessel wall to altered mechanics and disease. These properties influence the overall structure of vascular system during development and when altered contribute to vascular remodeling and development of pathologies. These stresses and their contribution to vascular mechanics have been reviewed and discussed in detail elsewhere (Humphrey, 2002, 2008b; Lehoux et al. Blood flow against the endothelial cells that line the vascular lumen causes a frictional force on the endothelial cells. This relationship illustrates that very slight changes in the diameter of a blood vessel can have dramatic effects on the shear stress to which the endothelial cells are exposed. This phenomenon plays an important role in short-term physiological adaptations to changes in blood flow and associated tissue perfusion and to long-term vascular remodeling. The primary adaptation to changes in shear stress is related to changes in the caliber of the blood vessels. Note the relationship between pressure and wall thickness, and radius and wall thickness, key components in the way in which different blood vessels respond to changes in transmural pressure and mechanisms of remodeling in response to changes in blood pressure. Typically, remodeling that occurs as a result of increased pressure is characterized by a decrease in vascular wall radius and/or increase in vascular wall thickness to maintain a constant level of wall stress. The existence of the axial force can easily be appreciated by the observation that when an artery is dissected from an animal it retracts to a length shorter than its in situ length, thus illustrating the contribution of the elastic elements to the overall stresses to which the vascular wall is exposed. Diverse data point to the concept of "mechanical homeostasis" in the vasculature and that during perturbations of the mechanical stresses mentioned above the blood vessels will attempt to maintain the stresses at a preferred value by reorganizing or remodeling the basic constituents of the blood vessel (Humphrey, 2008b). This concept is demonstrated at the tissue level as shown by the response to increases in blood flow above baseline results in an increased caliber of the vessel to maintain the shear stress at the desired homeostatic value. Similarly, vessels tend to increase wall thickness in response to sustained increases in circumferential wall stresses and vessels will lengthen in response to increases in axial stress (Dajnowiec and Langille, 2007). The various forms of mechanical stresses illustrated in these examples, implicate the role of mechanical homeostasis as a key regulator of vascular growth and remodeling and thus, contributes to the development of vascular pathologies. In this section we will introduce the various components of these systems and their role in the mechanotransduction system (Katsumi et al. Much research has focused on integrins as key components of the mechanoreceptor complex. For example, a5b1 binds fibronectin, avb3 binds vitronectin, and a1b1 and a2b1 bind to collagen and laminin. For example, activation of certain integrins leads to proliferation, while activation of others will influence cellular differentiation. Direct involvement of integrins in mechanotransduction was shown by coating magnetic beads with integrin-binding peptides or antibodies, allowing them to bind to the cell surface, and twisting them while monitoring cytoskeletal events (Wang and Ingber, 1995). More recently, atomic force microscopy has been used to probe the mechanical linkage between integrins and the cytoskeleton in vascular cells (Martinez-Lemus et al. In addition, focal adhesion sites form highly organized signaling molecule complexes, and the size and organization of these complexes is in part determined by the mechanical environment, thus making them prime candidates as mechanosensors and transducers. Mechanical Forces and Vascular Injury 285 the cytoskeleton and other structural components of the cell play an important role in mechanotransduction, because they are important in modulating and transmitting changes in tension within the cell. The cytoskeleton is composed of three major types of filaments: the microtubules, the microfilaments, and the intermediate filaments. Much attention has been focused on the microfilament system as part of the mechanosensor network. The microfilament system is composed of polymers of actin, actin-binding proteins, and other associated proteins. The actin cytoskeleton reorganizes in response to external stimuli, including vasoactive compounds that regulate the contractile status of the cells, and to changes in the mechanical environment. This cytoskeleton reorganization process can initiate signaling through the associated signaling molecules (Helmke, 2005). New evidence that will be discussed later in this article links directly the reorganization of the actin cytoskeleton to transcriptional pathways relevant to mechano-regulated alterations in vascular cell phenotype. Microtubules are dynamic protein polymers that are composed of tubulin molecules, which can polymerize and depolymerize to regulate cellular processes such as mitosis, cellular locomotion, vesicular transport, and organelle movement. Like the actin cytoskeleton, microtubules have been shown to reorganize in response to mechanical perturbations. Thus, flow and/or pressure-induced changes in microtubule assembly may result in altered vascular function. Thus, in addition to the actin cytoskeleton, microtubule organization may also be important in transmitting mechanical signals. The type of matrix, and hence the integrin dimer, which is activated directly regulates the downstream signaling patterns and thus plays an important role in the mechanotransduction pathways (Wells, 2008). The cadherins bind homophilically to cadherins on neighboring cells and like the integrins are linked to actin cytoskeleton through scaffolding molecules. Membrane rafts and caveolae have been implicated in mechanotransduction in a number of systems (Rizzo et al. Direct effects on G-protein-coupled receptors and ion channels have been implicated in the mechanotransduction pathways (White and Frangos, 2007). The specifics of these pathways have been presented in a number of excellent reviews and are beyond the scope of this article. While the ideas presented above focus on individual molecules, Ingber has proposed a "tensegrity" model to explain how organs, tissue, and cells sense and respond to changes in mechanical load. Tensegrity networks are composed of opposing tension and compression elements that ultimately balance each other. These structures create an internal prestress or resting tension that stabilizes the structure, which in the case of living organisms can be at the cellular, tissue, or organismal level. In the tensegrity model a local change in stress is borne by rearrangement of many prestressed elements that rearrange throughout the cell, rather than deforming and rearranging locally. These rearrangements occur without compromising the structural integrity of the cell. Thus, this organization provides a way to transmit mechanical forces along specific paths and to distant locales. The tensegrity model emphasizes that transmissions of mechanical forces cannot be understood by focusing on specific mechanosensitive molecules, which of course are important in their ability to sense mechanical load, but by focusing on the architectural organization of the cells and tissues involved. There are common elements to how various cells sense and respond to mechanical forces; however, there are also unique responses to specific types of mechanical stimulation and to the degree of stimulation. The next section will review the responses of endothelial cells and vessels to shear stress, the effects of cyclic mechanical strain and circumferential wall stresses on vascular cell response, and finally the effects of axial extension on vascular growth and remodeling. Murray has since used an optimization mathematical model to describe this phenomenon in which he 286 Mechanical Forces and Vascular Injury reasoned that the largest caliber vessel possible would reduce resistance and hence workload on the heart; whereas the metabolic burden to maintain a large supply of blood would suggest that the smallest caliber of vessel would be optimal. Based on these observations and theory, the ensuing years of research have focused on the biological mechanisms that are utilized to effectively modulate vessel caliber over both the short- and long-term in response to normal physiological processes and how these mechanisms and maladaptation may contribute to pathological vascular remodeling and vascular injury. Numerous studies have focused on the adaptation of arteries to changes in wall shear stresses mediated by changes in blood flow during normal physiological processes. To study the effect of these changes, various animal models have been developed to alter directly these variables. Changes in perfusion are major regulators of vessel growth and atrophy of blood vessels under many physiological situations in the adult organisms. This phenomenon is best illustrated by the rapid growth and remodeling of blood vessels during pregnancy when there is increased perfusion and their return to the pre-pregnancy state after pregnancy and the return to the normal perfusion. Remodeling of vasculature of the uterus during the different phases of the menstrual cycles also correspond to the required changes in perfusion (Hart et al. Additionally, changes in blood flow capacity and expected increases in the caliber of the affected arteries and numbers of microvessels are noted in response to the need for increased perfusion in response to long-term exercise training (Miyachi et al. An excellent review describing these and other examples was written by Langille (1996). However, lacking from these types of studies is the ability to distinguish between the multiple mechanisms that can contribute to vascular remodeling under these physiological conditions. A number of surgical techniques using animal models have been employed to begin to distinguish between the potential mechanisms regulating these processes and to isolate changes in shear stress as the major variable. For example, introduction of an arteriovenous shunt to increase blood flow through the carotid artery in rats resulted in a 75% increase in diameter as compared to the contralateral control. In contrast, placement of a stenosing ring around the common carotid artery to decrease blood flow in juvenile rats resulted in a delay in carotid artery growth and a 25% reduction in diameter. Additionally, a common method for studying direct effect of blood flow and shear stress on remodeling events is by altering the number of perfusions units in the mesenteric arcade by ligating contributing arteries. Using this approach, blood flow through these regions can be modified from 50% to 400% of the controls and the effect on vascular wall structure and the molecular mechanisms can be studied (Dajnowiec and Langille, 2007). Exposure of endothelial cells to varying levels of shear stress under controlled culture conditions has allowed for the identification of a number of signaling pathways and genes that are regulated by shear stress. Multiple methods have been used to expose cultured endothelial cells to altered shear stresses. The two most common methods are the use of the parallel plate flow system in which well-developed laminar flows are generated by a pump device over a confluent endothelial monolayer grown on a coverslip. The wall shear stress is a linear function of the volume flow rate through the channel (Chien, 2007). A broad dynamic range of shear forces can be generated by adjusting the medium viscosity, cone angle, and speed of rotation (Dewey et al. One of the first observations made regarding the cellular response to imposed shear stresses was that the cells align with the direction of flow. This observation has led to a hypothesis that cytoskeletal displacement and reorganization results in new interactions among signaling molecules by controlling their spatial proximity and conformational relationship to each other. The use of green fluorescent protein-tagged cytoskeleton proteins has allowed for the tracking of these changes in real time and interactions with other molecules. The general sets of signaling molecules described earlier in this article would be among the signaling molecules activated by shear stress (Helmke, 2005; Helmke and Davies, 2002). Gimbrone and coworkers were among the first to use this type of methodology coupled with microarray analysis to identify genes that were sensitive to changes in shear stress (Topper et al.

Neuronal activity in the medullary cardiac and vasomotor areas is influenced by afferent input from baroreceptors gastritis symptoms lower back pain generic biaxin 500 mg, chemoreceptors gastritis symptoms dogs biaxin 500 mg with visa, and various cardiac and pulmonary receptors as well as by input from the hypothalamus and cerebral cortex (Calaresu and Yardley gastritis diet advice nhs order biaxin 500 mg, 1988) gastritis diet 23 purchase 250 mg biaxin fast delivery. Descending fibers from the medulla transmit neural activity to preganglionic sympathetic and parasympathetic neurons via spinal roots and cranial nerves gastritis and coffee purchase generic biaxin from india, respectively gastritis food to eat cheap generic biaxin uk. The preganglionic sympathetic neurons synapse at the sympathetic chain and/or peripheral ganglia to relay efferent impulses to the cardiovascular and pulmonary systems via postganglionic fibers in somatic and autonomic nerves (Smith and Kampine, 1984). Whereas sympathetic postganglionic fibers are distributed to most of the vasculature, parasympathetic postganglionic fibers are less widely distributed and their preganglionic neurons synapse with them close to their target organs. Neurally mediated vasoconstrictor and vasodilator mechanisms vary widely among vascular beds due to differences in nerve fiber distribution, neurotransmitters, sensitivity and types of receptors, the contribution of resistance and capacitance vessels, and the balance between the degree of neural tone and local control mechanisms that influence the vascular response (Smith and Kampine, 1984). Although there is a range of responses in different vascular beds, the largest influence of the sympathetic division on the vasculature is an a-adrenergic-mediated constriction and a much more limited b-adrenergic dilator response in some tissues. Vasodilator fibers are not tonically active and are only distributed to some vascular beds. Mechanisms of vasodilation include sympathetic cholinergic vasodilation, which may occur in skeletal muscle and during the "defense" reaction. In addition, parasympathetic vasodilator fibers innervate pial vessels of the brain, salivary glands, some glands in the gastrointestinal tract, and the external genitalia. Other sympathetic postganglionic fibers travel in somatic and autonomic nerves to reach most arteries and veins of the body. Responses in skin, skeletal muscle, splanchnic, and renal vascular beds are especially significant. For a comprehensive review of peripheral autonomic neural pathways, see Gibbins (2012). Several other hypothalamic nuclei and extrahypothalamic structures are involved in the central autonomic network. For instance, the locus coeruleus (within the pons) is the primary nucleus of noradrenergic signaling and is involved in the processes of arousal and increased sympathetic output (Samuels and Szabadi, 2008). Whereas the hypothalamus is key to integrating cardiovascular responses, cortical sites influence hypothalamic integration via medullary cardiovascular areas and preganglionic sympathetic neurons. There is also a direct descending pathway from the hypothalamus to the spinal cord that bypasses the medulla. The sympathetic fight-or-flight response is centrally controlled in the cortex and hypothalamus and is associated with hypertension, tachycardia, and skeletal muscle vasodilation. The vasomotor center in the medulla and lower pons transmits sympathetic and parasympathetic neuronal activity to the heart. These pools of medullary neurons affect the firing rates of sympathetic and parasympathetic preganglionic neurons. The excitability of different medullary neuron pools may vary with afferent input, affecting firing rates of sympathetic and parasympathetic preganglionic neurons to cause greater effects in some vascular beds than in others. At a level below the medulla, efferent fiber distribution and innervation patterns also allow for differentiation of neurogenic cardiovascular responses. The increased tonic activity of neurons in the cerebrospinal vasoconstrictor regions increases action potential frequency in efferent fibers that innervate blood vessels, thereby causing vasoconstriction. The Role of the Autonomic Nervous System in Cardiovascular Toxicity 65 Normally, the vasoconstrictor area of the medullary vasomotor center is spontaneously active. Continuous activation of sympathetic nerve fibers provides a basal level of sympathetic vasomotor tone. As the vasomotor center sends activity to induce vasoconstriction, it also sends excitatory output to the heart via the lateral vasomotor center and then to sympathetic efferent fibers to increase heart rate, contractility, and lusitropy. Conversely, the medial vasomotor center activates vagal efferent fibers, which travel to the heart via the vagal nerves and decrease heart rate (chronotropy) and to some extent contractility. Together, these mechanisms coordinate the balance of sympathetic and parasympathetic activity that is transmitted to the heart. Increased sympathetic output to the vasculature usually occurs with increased sympathetic and decreased parasympathetic output to the heart. Conversely, decreased sympathetic output to the vasculature typically pairs with decreased sympathetic and increased parasympathetic output to the heart. Thus, the medulla influences the firing rate (activity) of sympathetic and parasympathetic preganglionic and postganglionic neurons, mediating cardiovascular effects in a coordinated way. Thus, many of the autonomic nerves carry both efferent nerve fibers directed by the central nervous system and afferent nerve fibers carrying information from sensory receptors. The end organ response varies with the prevalence and type of receptors and nerves. For instance, parasympathetic control of blood flow is generally limited when compared to sympathetic control because fewer blood vessels are innervated by postganglionic parasympathetic motor fibers. Catecholamines produced by neuroendocrine cells are often secreted into the blood in parallel with sympathetic activation. Complex interrelationships between substances at neuroeffector junctions also modify cardiovascular function. Sympathetic postganglionic fibers innervate various vascular beds differentially: sympathetic cholinergic vasodilator fibers are efferent nerves that are distributed to skeletal muscle. Parasympathetic cholinergic vasodilator fibers innervate some vascular beds such as the heart and certain cerebral arteries. One classic example of parasympathetic efferent-mediated vasodilation is found in reflexes to the stimulation of pulmonary chemosensitive receptors (Broten et al. In addition to neurotransmitters, these tissue receptors may be stimulated by circulating hormones such as catecholamines originating from the adrenal medulla. Muscarinic receptors induce intracellular signaling via their the Role of the Autonomic Nervous System in Cardiovascular Toxicity 67 coupling with G-proteins. In contrast, M2 and M4 receptors couple with Gi/o proteins, and M2 receptors also pair with Gq/11 and Gs proteins (Karakiulakis and Roth, 2012). Consequently, muscarinic receptor agonism or antagonism may initiate diverse and complex intracellular effects throughout the cardiopulmonary and vascular tissue. Additionally, stimulation of M5 receptors has been found to cause vasodilation in cerebral arteries, but not extracerebral arteries (Yamada et al. In airway smooth muscle cells, stimulation of respiratory M3 receptors induces bronchoconstriction and mucus secretion from submucosal glands likely contributing to chronic obstructive pulmonary disease (Karakiulakis and Roth, 2012) and potentially to asthma. Such postganglionic sympathetic cholinergic nerve endings may be found in blood vessels of skeletal muscle, where they promote vasodilation upon central sympathetic excitation. The effect is thought to be involved in certain emotional responses such as fright or rage and can be blocked by the muscarinic inhibitor atropine. Sympathetic cholinergic nerve activation has been indicated to cause vasodilation via release of nitric oxide (Davisson et al. They may also mediate secondary cardiovascular toxicity through toxin-induced respiratory dysfunction. Although their stimulation on human fibroblasts has been shown to promote proliferation of these cells, with the potential to exacerbate fibrosis (Turner et al. Here and in Table 1, we summarize the stimuli, receptors, neurons, and physiologic effects most pertinent to autonomic reflexes. In describing sensory receptors and their responses to various types of stimuli, our initial objective is to provide a perspective of the roles that the major types of cardiopulmonary receptors have in cardiovascular and pulmonary regulation. This knowledge comes from studies that elucidated receptor-mediated autonomic responses by using well-known stimuli to activate afferent pathways. In this introductory section, we have not included mechanisms by which the various stimuli activate the afferent receptors and signaling pathways that transduce responses in their nerve fibers. This topic is relevant in discussing mechanisms of cardiovascular toxicity to specific stimuli and comes later in this article. As nonselective cation channels, they affect membrane permeability and are involved in the process of excitation of sensory afferent nerve fibers in the cardiovascular and pulmonary systems. In addition to activation of afferent nerves in response to stimuli, they have significant roles in regulating cell functions important for mediating cardiopulmonary responses, including changes in heart function, vascular tone, and blood pressure regulation. The level of neural tone is also affected by other sites within the medulla and may be modulated by baroreceptor feedback in response to changes in pressure as well as by input from other types of cardiopulmonary receptors (Calaresu and Yardley, 1988). A number of reflexogenic zones can evoke cardiovascular effects in response to endogenous and exogenous stimuli. These zones have been characterized by the area in which they are located, the types of stimuli that activate the sensory nerves, neural pathways linking afferent and efferent reflex components, and by the nature of the reflex. Baroreceptor afferent nerve fibers from the receptors in the aortic arch and carotid sinuses increase their firing rates when stretched by increased arterial pressure. At low-pressure sites in the atria, stretch receptors monitor stretch or pressure changes associated with filling or volume and have been referred to as "volume receptors. Their responses compensate for changes in cardiac workload and vascular stress by inversely adjusting heart rate and vascular tone. As such, they modulate neural pathways key to maintaining cardiovascular homeostasis. It is important to note that baroreceptor (mechanoreceptor) input generally comprises input from myelinated and nonmyelinated sympathetic as well as parasympathetic fibers (Coleridge and Coleridge, 1980). Whereas sympathetic fibers are widely distributed in the heart, pericardium, venae cava, pulmonary artery and veins, and along the thoracic aorta, parasympathetic fibers are less diffusely distributed in these sensory areas. Decreases in blood pressure reduce baroreceptor impulse activity and subsequently disinhibit sympathetic adrenergic output from the medullary cardiovascular center to the blood vessels and heart, acting to increase blood pressure toward normal. Aortic baroreceptors include C-fiber as well as A-fiber afferents and it has been shown that C-fiber baroreceptors have higher thresholds, lower sensitivities, and maximum frequencies. Aortic A- and C-fiber baroreceptors discharge regularly with each cardiac cycle when their thresholds are reached. However, C-fiber baroreceptors have higher thresholds and appear to operate at a pressure range above the normal level. With frequent stimulation, an abrupt increase in pressure causes C-fiber baroreceptors to briefly discharge and reach a maximum frequency when arterial pressure is still increasing. Their overdamped and phase lagging dynamic characteristics may be due to the nature of their attachment to connective tissue elements, thus limiting their sustained activity. In contrast, A-fiber baroreceptors are rectified over a wide range of pulse frequencies. Baroreceptors at the carotid sinus transmit afferent signals via the carotid sinus nerve which increase in response to an increase in arterial pressure (stretch or vascular wall deformation in the area where the nerve endings are located) or decrease when pressure decreases. Normally, a burst of baroreceptor activity occurs during systole followed by a reduced frequency of discharge during diastole. The thresholds and sensitivities of the afferent nerve fibers to pressure changes vary and a stronger stimulus is signaled when more fibers are recruited. Pulsatile pressure causes a higher discharge rate than steady pressure and causes a greater inhibitory effect on tonic sympathetic discharge. The overall effect on a particular vascular bed varies with its pattern of innervation, type of vessels, and level of neural tone (Folkow and Neil, 1971; Smith and Kampine, 1984). At the aortic arch and right subclavian artery, baroreceptors are innervated by vagal afferent branches that travel in the aortic nerves (left and right respectively) to their cell bodies in the nodose ganglia and axons which project to the medulla. Like the carotid sinus nerves, activity in the aortic nerves is modulated by pressure changes during systole and diastole and has a tonic inhibitory influence on the medullary cardiovascular center. Aortic baroreceptors include C-fiber as well as Afiber afferents (Coleridge and Coleridge, 1980). The pulmonary artery and its branches are supplied by vagal fibers with receptors that have a baroreflex reflex function somewhat similar to that of the sinoaortic baroreceptor afferents so far as the systemic blood pressure is concerned. Due to their location, these receptors monitor a lower range of blood pressure and their influence on pulmonary arterial resistance or other vascular beds is not clear. Efferents terminating on the ventricular myocardium may also diminish contractility and relaxation. Their net effect causes vasodilation, decreased heart rate, strength of cardiac contraction, and rate of ventricular filling. Conversely, with a decrease in blood pressure, the resulting decreased activation of the baroreceptors diminishes their inhibitory effect on the vasoconstrictor center. As a result, sympathetic activity to the blood vessels and heart increases, while parasympathetic activity to the heart decreases. The arterial baroreceptors cause vasoconstriction predominately in arterial resistance vessels in the skeletal muscle, renal, and mesenteric vascular beds and in capacitance vessels in the splanchnic circulation (Coleridge and Coleridge, 1980; Folkow and Neil, 1971; Smith and Kampine, 1984). The reciprocal relationship between the parasympathetic and sympathetic efferents is exemplified by physiologic responses in cats to electrical stimulation of the parahypoglossal area of the medulla, which increases heart rate via both vagal withdrawal (confirmed with vagotomy) and sympathetic neural activation (confirmed with propranolol) (Calaresu and Henry, 1970). Moreover, while it is well appreciated that parasympathetic activation can inhibit sympathetic neurons, sympathetic activation has been shown to inhibit parasympathetic-mediated reflexes, including trigeminal-mediated vasodilation (Ishii et al. With regard to baroreceptors in general, it is also important to mention the phenomenon of baroreceptor resetting that alters their reflex response by increasing their threshold, decreasing their sensitivity, and maximal impulse frequency. Adaptation and postexcitatory depression of carotid baroreceptors can be caused by reversible viscoelastic changes induced by a stretch of the connective tissue attachments of the receptor terminals (Coleridge and Coleridge, 1980; Coleridge et al. Baroreceptor resetting develops progressively as hypertension develops and can be reversed at a relatively early stage. There is debate as to whether the Role of the Autonomic Nervous System in Cardiovascular Toxicity 71 baroreceptor resetting is entirely secondary to the increase in pressure (from other causes), or whether in some forms of hypertension, resetting plays a permissive role in allowing regulation of arterial pressure at increasingly higher levels. Their stimulation causes hyperventilation and generalized sympathetic vasoconstriction as well as vagal-mediated bradycardia. This primary reflex effect tends to increase blood pressure via sympathetic vasoconstriction especially in skeletal muscle, but not in the heart and brain, in order to maintain cardiac and cerebral perfusion. Overall, the chemoreflex acts to optimize oxygen delivery to the brain and heart via increased ventilation and decreased cardiac workload and output; however, with spontaneous breathing the increased lung movement causes a secondary reflex tachycardia and increased cardiac output. This is accompanied by a mixture of reflexively mediated vasoconstriction and vasodilation in various vascular beds.

Buy biaxin 250 mg overnight delivery. Conversion from Vertical Sleeve Gastrectomy to Functional One Anastomosis Gastric Bypass.