1,721,020 research outputs found
Ceramide signaling and tumor necrosis factor-alpha-induced vasodilation.
No full textCeramide is a sphingolipid second messenger generated both under basal conditions and via stimulation of a membrane-associated sphingomyelinase. Cytokines such as tumor necrosis factor-alpha (TNF-alpha) have been shown to stimulate ceramide synthesis in non-vascular cell types. TNF-alpha is a cytokine produced from cells of the immune system and of the vasculature in response to tissue injury. TNF-alpha elicits both endothelium-dependent and endothelium-independent vasodilation and is thought to play an important role in regulation of blood flow during inflammatory responses to injury. Therefore, determination of the cellular mechanisms by which TNF-alpha exerts its vascular effects represents a crucial area of research. The goal of this research was to characterize the role of the ceramide signaling pathway as a novel mechanism for mediating the vasodilatory actions of TNF-alpha in the vasculature. The general hypothesis of this dissertation is: Ceramide is a vasodilatory second messenger which mediates the vasodilatory effects of TNF-alpha in the vasculature. This hypothesis was tested by the following specific aims: (1) To determine whether ceramide itself is a vasodilator, (2) to determine whether TNF-alpha stimulates the ceramide signaling pathway in vascular smooth muscle, and (3) to determine the mechanism for ceramide regulation of vascular contractility. The main findings of this dissertation are that: (1) ceramide is an endothelium-dependent and -independent vasodilator, (2) TNF-alpha stimulates ceramide synthesis in vascular smooth muscle, (3) Both TNF-alpha-induced vasodilation and ceramide signaling are dependent upon phospholipase A2 activation, (4) ceramide may elicit vasodilation through inhibition of protein kinase C. The conclusion to be drawn from this dissertation is that TNF-alpha elicits vasodilation through activation of the ceramide signaling pathway. This pathway represents a novel signaling mechanism by which cytokines may induce a vasodilatory response thereby regulating blood flow and pressure.PhDAnimal PhysiologyBiological SciencesCellular biologyHealth and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131912/2/9938456.pd
Mechanisms of inhibition of vascular smooth muscle cell function by nitric oxide.
No full textNitric oxide (NO), an important biologic regulator of vascular function, is known to inhibit the growth of cultured vascular smooth muscle cells. The anti-proliferative mechanisms and cell cycle effects of nitric oxide remain undefined. This thesis tested the hypothesis that nitric oxide inhibits smooth muscle proliferation by inhibiting progression at a specific point in the cell cycle. The inhibitory effect of exogenous nitric oxide occurred during S phase in synchronized rat aortic smooth muscle cells. This S phase inhibition occurred after the restriction point of commitment to cell proliferation late in G1 phase, which is distinct from the point of inhibition of other endogenous inhibitors of proliferation. This S phase effect is not mimicked by cGMP, a second messenger for NO. The mechanism of S phase inhibition was partially reversed by bypass of ribonucleotide reductase, suggesting that inhibition by NO occurs at this point. In cycling cells NO caused immediate inhibition of DNA synthesis, confirming the effects seen in synchronized cells. Prolonged treatment with NO did not synchronize cells at the G1/S border, as hydroxyurea did, but instead induced a G0 state characterized by a prolonged delay before DNA synthesis resumed after removal of NO. This G0 state was not due to inhibition of either protein synthesis or mitochondrial respiration. NO donors also inhibited migration of smooth muscle cells in culture independent of inhibition of proliferation. This inhibition of migration was mimicked by an exogenous cGMP analog, suggesting the involvement of guanylate cyclase in mediating this effect. Inhibition of smooth muscle cell migration may be another mechanism by which NO inhibits neointimal hyperplasia in vivo. DNA synthesis and proliferation of cultured endothelial cells was also inhibited by NO donors at concentrations which inhibit smooth muscle proliferation. This may be one mechanism by which pathologic production of NO in diseased vessels inhibits re-endothelialization. NO is the first endogenous substance which inhibits cell growth in S phase, a process that may be important in regulation of proliferation of cells that have lost normal G1 mechanisms of growth control.PhDPhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/104700/1/9542951.pdfDescription of 9542951.pdf : Restricted to UM users only
Altered phosphoinositide metabolism and vascular reactivity in hypertensive rats.
No full textThe Ca messenger system has a central role in mediating vascular smooth muscle contraction. Hence, disorders in this system may underlie the development or maintenance of hypertension. This thesis examined the role of protein kinase C (PKC) and phosphoinositide (PI) metabolism, with respect to intracellular Ca, in arteries from hypertensive rats. Vascular reactivity to PKC activators (phorbol ester TPA and mezerein) in hypertensive rats was augmented compared to that in normotensive rats. This augmentation was observed in three models of hypertension: genetic; mineralocorticoid; and aortic coarctation. Verapamil (Ca-channel antagonist) and Ca-free solution relaxed arteries contracted with TPA. Sensitivity to verapamil in hypertensive arteries was greater than that in arteries from normotensive rats. This finding suggests that PKC activation leads to the opening of a greater number of Ca channels or a prolonged opening of channels in arteries from hypertensive rats. The influence of salt on increased vascular reactivity in mineralocorticoid (DOCA) hypertension was studied. Vascular responses to TPA in normotensive rats drinking high salt water were augmented compared to that in rats drinking tap water. DOCA treatment alone (normal salt diet) did not affect vascular reactivity. One week of DOCA-salt treatment did not influence blood pressure nor vascular responsiveness to TPA. Coarctation hypertension is a useful model for examining the effects of blood pressure on vascular function because the vasculature below the coarctation is not exposed to elevated pressure. Reactivity to TPA in thoracic aortae from coarctation-hypertensive rats was greater than that in aortae from normotensive rats. In contrast, responses to TPA in abdominal aortae from coarctation-hypertensive rats were not greater than normotensive values. These findings suggest that vascular reactivity to PKC activation is influenced by pressure per se. PI metabolism was measured as the release of (H) inositol phosphates in aortae from stroke-prone spontaneously hypertensive (SHRSP) and normotensive Wistar-Kyoto (WKY) rats. Serotonin-induced PI metabolism in aortae from SHRSP was greater than normotensive values. Contractile responses to serotonin were also augmented in SHRSP. Phospholipase C inhibition attenuated PI hydrolysis and depressed contraction. These results indicate that augmented PI metabolism contributes to increased vascular reactivity in hypertension.PhDAnimal PhysiologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/162138/1/8907159.pd
Cellular basis of inherited vascular defects in genetically hypertensive rats.
No full textThe mechanism of two genetically-inherited alterations in vascular function were studied by comparing responses of isolated blood vessels from the spontaneously hypertensive rat (SHR) and its stroke-prone substrain (SHR-SP), to those of normotensive, Wistar-Kyoto (WKY) controls. Previous experiments have demonstrated that both of the vascular responses studied are genetically associated with the blood pressure elevation observed in the SHR-SP. The isolated tail artery of the SHR-SP contracts to norepinephrine in an oscillatory fashion (1-3 cycles/min). The defect is unique to this rat strain and is inherited as an autosomal recessive trait. Simultaneous recording of contraction and membrane potential in these tissues indicate that the contractile phase of oscillations is associated with bursts of calcium-dependent action potentials. The relaxation phase of oscillations is associated with electrical quiescence. Potassium conductance plays an important role in regulating the automaticity of the tissue. Oscillations are inhibited by blocking potassium channels with barium (10M) and by elevation of extracellular potassium concentration (20mM). These interventions convert bursting electrical activity to tonic firing of action potentials. A toxin-sensitive (apamin, charybdotoxin), calcium-activated potassium conductance was not implicated in terminating bursts of action potentials. Aortic strips from the SHR or SHR-SP contract more rapidly in response to ouabain or potassium-free conditions than do tissues from WKY rats. These responses are completely dependent upon extracellular calcium sources. The difference in rate of contraction is not observed in the presence of verapamil (10M). Aortae from SHR display an enhanced calcium-sensitivity during ouabain-induced contraction. Both this enhanced calcium sensitivity and the increased rate of contraction to ouabain or potassium free buffer are no longer observed following exposure to calcium-free buffer containing ethylene glycol bis-(beta-aminoethyl ether) N,N,N,N-tetraacetic acid (EGTA). These results suggest that the enhanced responsiveness to ouabain and potassium-free solution which is observed in the SHR is related to increased calcium entry through verapamil-sensitive calcium channels. This defect may be related to a deficiency in smooth muscle membrane binding of calcium.PhDAnimal PhysiologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/162217/1/8920570.pd
Calcium and increased vascular reactivity in hypertension.
No full textEnhanced vascular reactivity in hypertension has been associated with a number of changes in cellular calcium handling. These studies examined potential-operated calcium channel function in hypertension and possible mechanisms that may underlie enhanced vascular sensitivity to catecholamines in this disorder. Contractile responses to the potential-operated calcium channel agonist, Bay K 8644, were markedly increased in thoracic aortic strips from coarctation-hypertensive rats as compared to those from normotensive sham rats. This effect was related to elevated arterial pressure since it was not seen in abdominal aortae from hypertensive rats, a vessel that is protected from increased pressure. The role of pressure per se was supported by findings of increased sensitivity to Bay K 8644 in abdominal aortae from 2 kidney 1 clip hypertensive rats. In this comparable model of hypertension, the abdominal aorta is exposed to elevated blood pressure. To evaluate channel function within the microvasculature, intracellular calcium concentration (Ca\sp{2+}) \sb{\rm i} was measured in rat pancreatic arterioles (15-35 m diameter) using microspectrofluorimetry of fura-2. In these vessels, KCl-induced increases in (Ca\sp{2+}) \sb{\rm i} were inhibited by nifedipine, consistent with activation of potential-operated calcium channels. Bay K 8644 evoked an increase in (Ca\sp{2+}) \sb{\rm i} in approximately 25% of arterioles tested from both genetically hypertensive and normotensive control rats. Neither basal (Ca\sp{2+}) \sb{\rm i} nor the change in (Ca\sp{2+}) \sb{\rm i} produced by Bay K 8644 differed between the two strains. However, since arterioles of this size are distal to the major resistance vessels, they may be protected from pressure-induced damage seen in larger arteries. Mechanisms that may account for enhanced vascular sensitivity to norepinephrine in mesenteric arteries from DOCA hypertensive rats were also examined. Agonist affinity and the calcium sensitivity of the contractile elements were not altered in these vessels, but norepinephrine-stimulated \sp{45}Ca\sp{2+} was increased, implicating a change in post receptor signal transduction involving calcium release from intracellular stores. In conclusion, these studies suggest that pressure-induced changes in potential-operated calcium channel function and augmented mobilization of intracellular calcium stores contribute to enhanced vascular reactivity in hypertension.PhDAnimal PhysiologyBiological SciencesHealth and Environmental SciencesNursingUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128908/2/9227012.pd
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Role of Rho -kinase -dependent constrictor activity in vascular smooth muscle.
No full textVascular tone is modulated by hormonal, neural and paracrine input for the proper regulation of blood pressure and organ perfusion. Elucidating and understanding the signaling pathway(s) involved in vascular smooth muscle contraction may aid in the prevention or successful treatment of many vascular-related end organ pathologies. Contraction of the smooth muscle cell occurs primarily via the Ca2+-dependent stimulation of myosin light chain (MLC) kinase, to lead to the phosphorylation of MLC and subsequent actin/myosin interaction. The phosphorylation of MLC is also regulated by the activity of MLC phosphatase, a process termed Ca2+-sensitization. MLC phosphatase activity is, in part, regulated by the small G-protein, RhoA, and a downstream target, Rho-kinase. The serine/threonine kinase, Rho-kinase, phosphorylates the myosin binding subunit of MLC phosphatase to inhibit phosphatase activity and thus promote the phosphorylated state of MLC. The goal of this dissertation was to determine the physiologic role and regulation of RhoA/Rho-kinase activity in vascular smooth muscle, following the general hypothesis that increased Rho-kinase activity promotes the maintenance of vasoconstriction and the inhibition of Rho-kinase signaling mediates vasodilation. Western blot analysis demonstrated RhoA and Rho-kinase protein expression in isolated rat cavernosal tissue. Using an in vivo rat model of erection, the intracavernosal injection of Y-27632, a selective Rho-kinase inhibitor, was found to result in a significant increase in intracavernosal pressure/mean arterial pressure. In vitro measurements of isometric force generation demonstrated Y-27632 to relax agonist-induced contraction of isolated rat cavernosal tissue and aorta. Additional measurements of isometric force generation of rat aorta found the inhibitory effects of Y-27632 to be attenuated in the absence of nitric oxide production or signaling, consistent with the hypothesis that Rho-kinase activity is elevated in the absence of nitric oxide. Data presented in this dissertation demonstrate a role for Rho-kinase activity in the maintenance of vascular smooth muscle contraction and provide evidence to support that the inhibition of Rho-kinase activity is a physiologic mechanism of nitric oxide-induced vasodilation.PhDAnimal PhysiologyBiological SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131555/2/3057921.pd
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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