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Endothelial Cell Function (endothelial + cell_function)
Selected AbstractsAngiotensin II regulates endothelial cell migration through calcium influx via T-type calcium channel in human umbilical vein endothelial cellsACTA PHYSIOLOGICA, Issue 4 2010A. Martini Abstract Aim:, The T-type calcium channel is expressed in vascular endothelial cells, but its role in endothelial cell function is yet to be elucidated. We analysed the endothelial functional role of T-type calcium channel-dependent calcium under angiotensin II (Ang II) stimulation. Methods:, Human umbilical vein endothelial cells were co-incubated with hormone at 10,7 m and either Efonidipine 10,5 m or Verapamil 10,5 m or Mibefradil 10,5 m or Wortmannin 10,6 m. The contribution of Ang II receptors was evaluated using PD123319 10,7 m and ZD 7155 10,7 m. The calcium ion concentration was observed using Fluo-3 acetossimetil ester. The cells were observed after 3, 6, 9 and 12 h. Results:, The microfluorescence method points out that Ang II induces intracellular calcium modulation in time by distinct mechanisms. AT2 receptor blockade is necessary to observe significant increase in [Ca2+]i levels. Pre-treatment with Mibefradil abolishes Ang II -induced cell migration. Conclusions:, Our data show that Ang II, via AT1 receptor, modulates calcium concentration involving T-type calcium channel and L-type calcium channel but only the calcium influx via T-type calcium channels regulates endothelial cell migration which is essential for angiogenesis. [source] Role of aquaporins in endothelial water transportJOURNAL OF ANATOMY, Issue 5 2002A. S. Verkman The aquaporins (AQP) are a family of homologous water channels expressed in many epithelial and endothelial cell types involved in fluid transport. AQP1 protein is strongly expressed in most microvascular endothelia outside of the brain as well as in endothelial cells in cornea, intestinal lacteals, and other tissues. AQP4 is expressed in astroglial foot processes adjacent to endothelial cells in the central nervous system. Transgenic mice lacking aquaporins have been useful in defining their role in mammalian physiology. Mice lacking AQP1 manifest defective urinary concentrating ability, in part because of decreased water permeability in renal vasa recta microvessels. These mice also show a defect in dietary fat processing that may involve chylomicron absorption by intestinal lacteals. There is preliminary evidence that AQP1 might play a role in tumour angiogenesis and in renal microvessel structural adaptation. However AQP1 in most endothelial tissues does not appear to have a physiological function despite its role in osmotically driven water transport. For example mice lacking AQP1 have low alveolar capillary water permeability but unimpaired lung fluid absorption, as well as unimpaired saliva and tear secretion, aqueous fluid outflow, and pleural and peritoneal fluid transport. In the central nervous system mice lacking AQP4 are partially protected from brain oedema in water intoxication and ischaemic models of brain injury. Therefore although the role of aquaporins in epithelial fluid transport is in most cases well understood there remain many questions about the role of aquaporins in endothelial cell function. It is unclear why many leaky microvessels strongly express AQP1 without apparent functional significance. Improved understanding of aquaporin endothelial biology may lead to novel therapies for human disease, such as pharmacological modulation of tumour angiogenesis, renal fluid clearance and intestinal absorption. [source] Critical role of the vascular endothelial cell in health and disease: a review articleJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 2 2004Todd C. Duffy DVM Abstract Objective: To review the human and veterinary literature on the role of the vascular endothelial cell in health, as well as during hypoxic and inflammatory disease states. Data sources: Data from human and veterinary literature were reviewed through a Pubmed search and a manual search of the references listed in articles covering some aspect of vascular endothelial cell function. Human data synthesis: The development of techniques that allow the maintenance and growth of endothelial cells in culture has produced an explosion of new research in the area of endothelial cell physiology. This plethora of data has revealed the critical role that vascular endothelial cells play in both health and disease states. Interspecies variations can occur with respect to the vascular endothelial cell physiology and its response to pathologic conditions. Veterinary data synthesis: There is a paucity of information regarding the role of the vascular endothelial cell in health or disease of small animals. Many human studies use species cared for by veterinarians, providing information that may be applied to small animals and that may be used to construct future studies. Conclusion: An organ system itself, the vascular endothelium is an essential component of all organs in the body. The endothelial cell lining functions to maintain selective permeability between the blood and the tissue it supplies, regulate vascular tone, sustain blood fluidity through regulation of coagulation, and modulate interaction of leukocytes with the interstitium and inflammatory reactions. During disease states, the endothelial cell functions locally to limit the boundaries of the disease process. If these functions are not controlled, they can become a part of the pathogenic process, contributing to blood stasis and thrombosis, potentiation of local inflammation and interstitial edema formation, subsequent tissue hypoxia, and multiple organ dysfunction. Pharmacological investigations targeting the modulation of endothelial function during disease states have not yet advanced treatment protocols. Since all critically ill animals are at risk for some degree of endothelial cell dysfunction, treatment regimens should focus on promoting capillary blood flow and tissue oxygen delivery. [source] Ischemia,Reperfusion Impairs Ascending Vasodilation in Feed Arteries of Hamster Skeletal MuscleMICROCIRCULATION, Issue 7 2005MIRIAM C. J. DE WITH ABSTRACT Objective: Vasodilation originating within the microcirculation ascends into proximal feed arteries during muscle contraction to attain peak levels of muscle blood flow. Ascending vasodilation (AVD) requires an intact endothelium, as does conducted vasodilation in response to acetylcholine (ACh). Whereas ischemia,reperfusion (I-R) can affect endothelial cell function, the effect of I-R on AVD is unknown. The authors tested the hypothesis that I-R (1h,1h) would impair AVD. Methods: Using the retractor muscle of anesthetized hamsters, contractions were evoked using field stimulation (200 ms at 40 Hz every 2 s for 1 min) and ACh was delivered using microiontophoresis (1 ,m tip, 500,4000 ms pulse at 800 nA). Feed artery responses were monitored 500,1500 ,m upstream. Results: Neither resting (51 ± 4 ,m) nor maximal diameter (81 ± 5 ,m; 10 ,m sodium nitroprusside) following I-R (n = 8) were different from time-matched controls (n = 10). With peak active tension of 23 ± 4 mN · mm,2, control AVD was 26 ± 2 ,m. Following I-R, active tension fell by 48% (p < .05) and AVD by 57% (p < .05). Stimulation at 70 Hz restored active tension but AVD remained depressed by nearly half (p < .05), as did local and conducted responses to ACh. Nevertheless, control responses to 500 ms ACh were restored by increasing stimulus duration to 4000 ms. Conclusions: Ischemia,reperfusion impairs the initiation of feed artery dilation with muscle contraction and with ACh while conduction along the vessel wall is preserved. Respective components of endothelial cell signaling events may differ in their susceptibility to I-R. [source] Regulation of Blood Flow in the MicrocirculationMICROCIRCULATION, Issue 1 2005STEVEN S. SEGAL ABSTRACT The regulation of blood flow has rich history of investigation and is exemplified in exercising skeletal muscle by a concerted interaction between striated muscle fibers and their microvascular supply. This review considers blood flow control in light of the regulation of capillary perfusion by and among terminal arterioles, the distribution of blood flow in arteriolar networks according to metabolic and hemodynamic feedback from active muscle fibers, and the balance between peak muscle blood flow and arterial blood pressure by sympathetic nerve activity. As metabolic demand increases, the locus of regulating oxygen delivery to muscle fibers "ascends" from terminal arterioles, through intermediate distributing arterioles, and into the proximal arterioles and feed arteries, which govern total flow into a muscle. At multiple levels, venules are positioned to provide feedback to nearby arterioles regarding the metabolic state of the tissue through the convection and production of vasodilator stimuli. Electrical signals initiated on smooth muscle and endothelial cells can travel rapidly for millimeters through cell-to-cell conduction via gap junction channels, rapidly coordinating vasodilator responses that govern the distribution and magnitude of blood flow to active muscle fibers. Sympathetic constriction of proximal arterioles and feed arteries can restrict functional hyperemia while dilation prevails in distal arterioles to promote oxygen extraction. With vasomotor tone reflecting myogenic contraction of smooth muscle cells modulated by flow-induced vasodilator production by endothelium, the initiation of functional vasodilation and its modulation by shear stress and sympathetic innervation dictate how and where blood flow is distributed in microvascular networks. A remarkable ensemble of signaling pathways underlie the integration of smooth muscle and endothelial cell function in microvascular networks. These pathways are being defined with new insight as novel approaches are applied to understanding the cellular and molecular mechanisms of blood flow control. [source] Regulation of bone morphogenetic protein signalling in human pulmonary vascular development,THE JOURNAL OF PATHOLOGY, Issue 1 2008M Southwood Abstract The bone morphogenetic protein (BMP) type II receptor (BMPR-II) is predominantly expressed on the vascular endothelium in the adult lung. Although mutations in BMPR-II are known to underlie many cases of familial pulmonary arterial hypertension (FPAH), little is known regarding the expression of BMPs and their signalling pathways during normal lung development or the impact of BMPR-II mutations on endothelial cell function. We determined the cellular localization and expression levels of BMP4, BMP receptors, and activation of downstream signalling via phospho-Smad1 in a developmental series of human embryonic and fetal lungs by immunohistochemistry. The expression of BMP4 and BMP receptors was temporally and spatially regulated during lung development. BMPR-II expression correlated with phosphorylation of tissue Smad1 and was highest during the late pseudoglandular and early canalicular stage of lung development, when vasculogenesis is intense. Phospho-Smad1 expression was associated with markers of proliferation in endothelial cells. In vitro studies confirmed that BMPs 2 and 4 induced phosphorylation of Smad1/5 and pulmonary artery endothelial cell (PAEC) migration and proliferation. Adenoviral transfection of PAECs with mutant kinase-deficient BMPR-II, or siRNA knockdown of BMPR-II, inhibited Smad signalling and the proliferative response to BMP4. Our findings support a critical role for BMPs in lung vasculogenesis. Dysfunctional BMP signalling in PAECs during development may lead to abnormal pulmonary vascular development and contribute to the pathogenesis of FPAH. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Low-molecular-weight heparins and angiogenesis,APMIS, Issue 2 2006KLAS NORRBY The involvement of the vascular system in malignancy encompasses not only angiogenesis, but also systemic hypercoagulability and a pro-thrombotic state, and there is increasing evidence that pathways of blood coagulation and angiogenesis are reciprocally linked. In fact, cancer atients often display hypercoagulability resulting in markedly increased thromboembolism, which requires anti-coagulant treatment using heparins, for example. Clinical trials reveal that treatment with various low-molecular-weight heparins (LMWHs) improves the survival time in cancer patients receiving chemotherapy compared with those receiving unfractionated standard heparin (UFH) or no heparin treatment, as well as in cancer patients receiving LMWH as thrombosis prophylaxis during primary surgery. This anti-tumor effect of the heparins appears to be unrelated to their anti-coagulant activity, but the mechanisms involved are not fully understood. Tumor growth and spread are dependent on angiogenesis and it is noteworthy that the most potent endogenous pro- and anti-angiogenic factors are heparin-binding proteins that may be affected by systemic treatment with heparins. Heparin and other glycosaminoglycans play a role in vascular endothelial cell function, as they are able to modulate the activities of angiogenic growth factors by facilitating the interaction with their receptor and promoting receptor activation. To date, preclinical studies have demonstrated that only LMWH fragments produced by the heparinase digestion of UFH, i.e. tinzaparin, exert anti-angiogenic effects in any type of tissue in vivo. These effects are fragment-mass-specific and angiogenesis-type-specific. Data on the effect of various LMWHs and UFH on endothelial cell capillary tube formation and proliferation in vitro are also presented. We hope that this paper will stimulate and facilitate future research designed to elucidate whether the anti-angiogenic or anti-tumor effects of commercial LMWHs in their own right are agent specific and whether anti-angiogenic properties increase the anti-tumor properties of the LMWHs in the clinic. [source] Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell functionARTHRITIS & RHEUMATISM, Issue 8 2009Lars Stangenberg Objective To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. Methods The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin,selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil,endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. Results SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor , was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. Conclusion A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions. [source] Activin ,A -subunit and activin receptors in human myometrium at term and during labourBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 8 2001Michal Schneider-Kolsky Objective To measure activin A content and to localise and semi-quantitate activin receptors in human myometrium at term and during labour. Design Myometrium was collected from non-pregnant women (n= 6), pregnant women at term not in labour (n= 6) and at term in labour (n= 6). Setting Monash Medical Centre, Melbourne, Australia. Main outcome measures Tissue lysates of myometrium were analysed for activin A content using an enzyme-linked immunosorbent assay and activin receptor proteins IA, IIA and IIB using Western hybridisation. Activin ,A -subunit and activin receptors were localised in myometrium by immunohistochemistry. Results Activin A was detected by ELISA in non-pregnant, pregnant and labouring myometrium. Levels were significantly higher in labouring myometrium. The three activin receptors IA, IIA and IIB were detected in all myometrial samples by Western hybridisation. Receptor IA was expressed in significantly higher levels in pregnant myometrium. Receptor IIA was very weakly expressed throughout. The expression of receptor IIB was similar in all three groups. Activin ,A -subunit and all three receptors were localised to the endothelial cells of myometrial blood vessels. Neither activin ,A -subunit nor any of the three activin receptors were immunolocalised to myometrial smooth muscle cells in the three groups. This result was confirmed by Western blotting for expression of activin receptors in isolated myometrial smooth muscle and microvascular endothelial cells. Conclusion The myometrium is not a target for activin A during late pregnancy or labour. However, activin A may have a role in the regulation of microvascular endothelial cell function in the myometrium. [source] Prediction of posthepatectomy hepatic functional reserve by serum hyaluronateBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 5 2009S. Yachida Background: Serum hyaluronate can be used as an index of hepatic sinusoidal endothelial cell function and hepatic fibrosis. This study was designed to clarify the clinical significance of the serum hyaluronate level as a parameter of functional reserve. Methods: The study included 283 patients undergoing hepatectomy. Liver function parameters were examined before surgery and compared with outcomes. Patients were retrospectively grouped according to the presence or absence of postoperative hepatic dysfunction. Results: Preoperative serum hyaluronate levels were significantly raised in parallel with the degree of severity of the underlying chronic liver disease. Regression analysis revealed serum hyaluronate level to be an independent predictor of portal hypertension. In 131 patients undergoing major hepatectomy, preoperative hyaluronate levels were significantly higher in patients with poor outcome. Multivariable logistic regression analysis demonstrated serum hyaluronate and total bilirubin levels to be independent variables associated with postoperative hepatic dysfunction. Patients with high indocyanine green retention rate at 15 min (over 15 per cent) showed significantly higher morbidity and mortality rates when their serum hyaluronate levels were over 180 ng/ml. Conclusion: Serum hyaluronate is a simple clinical marker for portal venous pressure and a reliable auxiliary parameter of hepatic functional reserve in combination with other liver function tests. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Alcohol And Endothelial Function: A Brief ReviewCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2001IB Puddey SUMMARY 1. In spite of the dose-related effects of alcohol consumption to increase blood pressure, regular light to moderate alcohol intake appears to confer protection against both coronary artery disease and ischaemic stroke. In contrast, heavy alcohol consumption increases the risk of coronary artery disease and the risk of both haemorrhagic and ischaemic stroke. 2. Effects of alcohol consumption on endothelial cell function may be relevant to these disparate effects on cardiovascular outcomes. In in vitro animal studies, low doses of alcohol have been demonstrated to increase release of nitric oxide and augment endothelium-mediated vasodilatation, whereas higher doses impair endothelium-dependent relaxation responses. In contrast, chronic administration of alcohol to rats has generally been associated with tolerance to the acute inhibitory effects of alcohol on endothelium-mediated vasodilatation and may even result in augmentation of such responses. 3. The few human studies to date that have examined the effects of alcohol on endothelial function have focused on postischaemic flow-mediated dilation of the brachial artery (FMD). Although blunted FMD responses have been reported in alcoholic subjects, acute administration of alcohol or short-term interventions to reduce alcohol intake have had no effect to either improve or impair FMD. 4. Further studies in humans assessing acute and longer term dose-related effects of alcohol on endothelial function in both conduit and resistance vessels will be necessary if the relevance of the findings from in vitro and in vivo animal studies are to be understood in the context of the complex interrelationships of alcohol with cardiovascular disease. [source] Effects of stent coating on platelets and endothelial cells after intracoronary stent implantationCLINICAL CARDIOLOGY, Issue 2 2001Enver Atalar M.D. Abstract Background: Adhesion molecules are known to be important in the regulation of endothelial cell and platelet functions. Increased platelets P-selectin expression is a marker of stent thrombosis after uncoated stent placement. Hypothesis: The aim of this study was to compare the effects of intracoronary placement of phosphorylcholine (PC)-coated, versus heparin-coated, versus uncoated stents on platelets and endothelial activity. Methods: Thirty patients (age 55 ± 10, 27 men) with significant proximal left anterior descending coronary artery stenoses were randomized to elective implantation of PC-coated. versus heparin-coated. versus uncoated stents. Following stent placement, intravenous heparin and aspirin plus ticlopidine were administered. Venous plasma soluble E-selectin, sP-sclectin, and intercellular adhesion molecule-1 levels were measured before the procedure and 24 and 48 h thereafter as markers of platelet and endothelial cell activation. Patients were excluded if they had a disease known to influence platelet and endothelial cell function. Results: Plasma sP-selectin levels decreased significantly after implantation of PC- and heparin-coated stents (p = 0.04), hut remained unchanged in patients randomized to uncoated stents. Plasma sE-selectin levels increased significantly after uncoated stent placement (p = 0.04) and remained unchanged after coated stent implantation. Conclusion: In patients treated with combined antiplatelet therapy, implantation of PC- and heparin-coated stents decreased platelet activity without activating endothelial cells, whereas placement of uncoated stents led to endothelial activation without changing platelet activity. These results suggest that PC-coated and heparin-coated stents may be advantageous in limiting thrombotic complications. [source] Pyrazolo,pyrimidine-derived c-Src inhibitor reduces angiogenesis and survival of squamous carcinoma cells by suppressing vascular endothelial growth factor production and signalingINTERNATIONAL JOURNAL OF CANCER, Issue 5 2007Sandra Donnini Abstract Src tyrosine kinase family cooperates with activated growth factor receptors to regulate growth, invasion and metastasis. The authors examined the influence of a novel c-Src inhibitor, 1l, derived from 4-amino-substituted-pyrazolo,pyrimidines, on tumor angiogenesis and on the angiogenic output of squamous carcinoma cells, A431 and SCC-4. The effect of 1l was assessed on growth and microvessel density in A431 tumors and its effect compared with the established c-Src inhibitor PP-1. The effects of c-Src inhibition were investigated on vascular endothelial growth factor (VEGF) expression and activity in tumor cells grown in vivo and in vitro, as well as on VEGF mediated signaling and on endothelial cell functions. Nanomolar concentrations of 1l decreased tumor volume promoted by A431 implanted in nude mice, without affecting in vitro cell tumor survival. This effect was related to 1l inhibition of VEGF production, and secondary to an effect on tumor microvessel density. The rabbit cornea assay confirmed that 1l markedly decreased neovessel growth induced by VEGF. In cultured endothelial cells, 1l inhibited the VEGF-induced phosphorylation on tyr416 of c-Src, resulting in a reduced cell proliferation and invasion. Consistently, 1l dowregulated endothelial nitric oxide synthase, MAPK-extracellular receptor kinase 1,2 (ERK1-2) activity and matrix metalloproteinases (MMP-2/MMP-9), while the tissue inhibitors of metalloproteinases (TIMP2/TIMP-1) were upregulated. These results demonstrate that nM concentrations of c-Src kinase inhibitors (1l and PP-1), by reducing the production of VEGF released by tumor cell and its endothelial cell responses, have a highly selective antiangiogenesis effect, which might be useful in combination therapies. © 2006 Wiley-Liss, Inc. [source] Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivoJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 10 2009Paulius Venalis Abstract Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc. [source] Dopamine modulates von Willebrand factor secretion in endothelial cells via D2,D4 receptorsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2006S. ZAREI Summary.,Objective: von Willebrand factor (VWF) is acutely released from endothelial cells in response to numerous calcium-raising agents (e.g. thrombin, histamine) and cAMP-raising agents (e.g. epinephrine, adenosine, vasopressin). In contrast, very few inhibitors of endothelial VWF secretion have been described. The neurotransmitter dopamine is a modulator of exocytosis in several endocrine cells, and is possibly involved in the regulation of several endothelial cell functions. We therefore investigated the effect of dopamine on endothelial VWF secretion. Results: Dopamine, D2/D3- and D4-specific agonists inhibited histamine- but not thrombin-induced VWF secretion. Expression of dopamine D2, D3 and D4 receptors was demonstrated by reverse transcription polymerase chain reaction (RT-PCR) in both human aortic (HAEC) and umbilical vein (HUVEC) endothelial cells. D2,D4 agonists did not inhibit histamine-induced rise in [Ca2+]i: they inhibited histamine-induced secretion even in the absence of extracellular calcium. Thus, the dopamine effects are not mediated by [Ca2+]i -dependent signalling. D2/D3- and D4-specific agonists inhibited neither the rise in cAMP nor VWF secretion in response to epinephrine and adenosine, arguing against an effect on cAMP-mediated signalling. D1 and D5 receptors were not detected in HAEC or HUVEC by RT-PCR, and the D1/D5-specific agonist SKF 38 393 failed to modulate VWF secretion, arguing against a role for these receptors in endothelial exocytosis. Conclusions: Dopamine inhibits histamine-induced endothelial exocytosis by activating D2,D4 receptor, via a mechanism distinct from [Ca2+]i -or cAMP-mediated signaling. In contrast, D1 and D5 receptors are not functionally expressed in cultured endothelial cells. Dopamine agonists may be useful as inhibitors of endothelial activation in inflammation and cardiovascular disease. [source] Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell functionARTHRITIS & RHEUMATISM, Issue 8 2009Lars Stangenberg Objective To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. Methods The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin,selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil,endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. Results SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor , was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. Conclusion A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions. [source] 3352: The effects of high altitude on central corneal thicknessACTA OPHTHALMOLOGICA, Issue 2010H BASMAK Purpose A large number of people are exposed to long-term hypobaric hypoxic conditions via mountaineering, skiing and trekking. Other people such as aviators and high-altitude parachutists are exposed to short-term hypobaric hypoxic conditions. It is known that hypobaric conditions alter physiological and morphological status of the eye including the central corneal thickness (CCT). Our aim is to review the results of the influences of high altitude on CCT. We will also add our experience on the influences of short-term hypobaric hypoxia on CCT. Methods Reports covering this topic will be discussed. The possible mechanisms for the alterations in CCT will be included. Hypobaric hypoxic conditions simulate high altitudinal environments, which was the basis of our study covering 70 eyes of 35 healthy men exposed to hypobaric hypoxic condition. We measured the CCT via ultrasound pachmetry at local ground (792 m above sea level) and then during short-term hypobaric hypoxic exposure (equivalent 9144 m above). Results CCT has been found to be increased at high altitudes. We also found that hypobaric hypoxic condition increased the CCT significantly. The mechanism of increased CCT is not clear, although the alterations in corneal endothelial cells function seem to be the main explanation. Systemic delivery of oxygen to the anterior chamber can possibly be an important contributing factor based on a recent study. Conclusion CCT has been reported to be increased at high altitude. The possible underlying mechanisms are altered endothelial function and metabolic activity. [source] | |||||||||||||