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Vascular Wall (vascular + wall)
Selected AbstractsIbudilast: A Non-selective PDE Inhibitor with Multiple Actions on Blood Cells and the Vascular WallCARDIOVASCULAR THERAPEUTICS, Issue 3 2001Yukio Kishi ABSTRACT Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is widely used in Japan for improving prognosis and relieving symptoms in patients suffering from ischemic stroke or bronchial asthma. These clinical applications are based on the properties of ibudilast that inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory actvity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks. Ibudilast was also reported to significantly attenuate inflammatory cell infiltration in the lumbar spinal cord in an animal model of encephalomyelitis. Future investigations should include effects of ibudilast on inflammatory reactions between endothelium and blood cells, which may initiate the development of atherosclerosis. [source] Lowered albumin extravasation rate in heart but not in other organs in ,3-integrin-deficient miceACTA PHYSIOLOGICA, Issue 4 2009Ø. S. Svendsen Abstract Aim:, The vascular protein permeability is dependent on the integrity of the vascular wall. The heart capillaries in male mice lacking ,3 integrins have an immature phenotype. Previously, we have demonstrated a role for ,v,3 integrins in control of interstitial fluid pressure (Pif) and thereby in the fluid flux during inflammation. We wanted to explore a possible role for ,v,3 integrins in controlling capillary protein permeability during control situation and inflammation. Methods:, We performed double-tracer and microdialysis experiments on ,3-integrin-deficient mice and wild type control mice. We also measured blood pressure and heart rate in the two mice strains. Results:, We found reduced albumin extravasation (during 25 min) in the heart capillaries (0.053 ± 0.003 vs. 0.087 ± 0.009 mL g,1 dw, P < 0.05), and an increased cardiac mass/body weight (5.3 × 10,3 ± 0.3 × 10,3 vs. 3.8 × 10,3 ± 0.1 × 10,3, P < 0.01) in the ,3-integrin-deficient mice (n = 6) compared with the controls (n = 6). Heart rate and blood pressure were the same in mice with and without ,3-integrins. No difference in permeability was found in other tissues studied, or under local inflammation. Conclusion:, These results show a function for the ,v,3 integrin in the regulation of protein permeability, selective for the heart capillaries. [source] Platelet-derived growth factor receptors expressed in response to injury of differentiated vascular smooth muscle in vitro: effects on Ca2+ and growth signalsACTA PHYSIOLOGICA, Issue 2 2001A. Lindqvist Vascular smooth muscle cells (VSMCs) in the intact vascular wall are differentiated for contraction, whereas the response to vascular injury involves transition towards a synthetic phenotype, with increased tendency for proliferation. Platelet-derived growth factor (PDGF) is thought to be important for this process. We investigated expression and functional coupling of PDGF receptors (PDGFRs) , and , in rat tail arterial rings kept in organ culture, in order to capture early events in the phenotypic transition. In freshly dissected rings no PDGFR immunoreactivity was found in medial VSMCs, whereas PDGFR , was detected in nerve fibres. After organ culture for 1,4 days PDGFR , and , as well as phospholipase C,2 (PLC,2), known to couple to PDGFR, were expressed in VSMCs within 100 ,m of the cut ends. Calponin, a marker for the contractile phenotype, was decreased near the injured area, suggesting that cells were in transition towards synthetic phenotype. In these cells, which showed functional Ca2+ -release from the sarcoplasmic reticulum, PDGF-AB (100 ng mL,1) had no effect on [Ca2+]i, whereas cultured VSMCs obtained from explants of rat tail arterial rings responded to PDGF-AB with an increase in [Ca2+]i. However, PDGFR within the cultured rings coupled to growth signalling pathways, as PDGF-AB caused a tyrphostin AG1295-sensitive activation of extracellular signal-regulated kinases 1 and 2 and of [3H]-thymidine incorporation. Thus, early expression of PDGFR in VSMC adjacent to sites of vascular injury coincides with signs of dedifferentiation. These receptors couple to growth signalling, but do not activate intracellular Ca2+ release. [source] Structural and biophysical simulation of angiogenesis and vascular remodeling ,DEVELOPMENTAL DYNAMICS, Issue 4 2001Ralf Gödde Abstract The purpose of this report is to introduce a new computer model for the simulation of microvascular growth and remodeling into arteries and veins that imitates angiogenesis and blood flow in real vascular plexuses. A C++ computer program was developed based on geometric and biophysical initial and boundary conditions. Geometry was defined on a two-dimensional isometric grid by using defined sources and drains and elementary bifurcations that were able to proliferate or to regress under the influence of random and deterministic processes. Biophysics was defined by pressure, flow, and velocity distributions in the network by using the nodal-admittance-matrix-method, and accounting for hemodynamic peculiarities like Fahraeus-Lindqvist effect and exchange with extravascular tissue. The proposed model is the first to simulate interdigitation between the terminal branches of arterial and venous trees. This was achieved by inclusion of vessel regression and anastomosis in the capillary plexus and by remodeling in dependence from hemodynamics. The choice of regulatory properties influences the resulting vascular patterns. The model predicts interdigitating arteriovenous patterning if shear stress-dependent but not pressure-dependent remodeling was applied. By approximating the variability of natural vascular patterns, we hope to better understand homogeneity of transport, spatial distribution of hemodynamic properties and biomass allocation to the vascular wall or blood during development, or during evolution of circulatory systems. © 2001 Wiley-Liss, Inc. [source] Inflamed adipose tissue, insulin resistance and vascular injuryDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 8 2008Christian X. Andersson Abstract Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system. Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall. Copyright © 2008 John Wiley & Sons, Ltd. [source] Adrenomedullin and diabetes mellitusDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2001Eva Ruzicska Abstract Adrenomedullin (AM) is a novel 52 amino acid peptide hormone, originally isolated from human pheochromocytoma. AM acts as a local autocrine and/or paracrine vasoactive hormone and has vasodilator and blood pressure lowering properties. AM as a vasodilative molecule protects the vascular wall but its exact role is still uncertain. AM is considered to play an important endocrine role in various tissues in maintaining electrolyte and fluid homeostasis. Its plasma concentration in healthy conditions is low. In hypertension, chronic renal failure and congestive heart failure its plasma concentration increases in a parallel manner with the severity of the disease. It is assumed that this peptide plays an important role in physiological and pathological conditions compensating the effects of vasoconstrictive molecules. Investigations have proven that in diabetic angiopathies the levels and production of vasoconstrictive factors and AM are increased, while other relaxing substances such as nitric oxide (NO) are decreased. It is still uncertain whether the increased release of AM is a compensatory mechanism or a coincidental event. Although the precise role of AM in the pathogenesis of diabetic complications is still to be elucidated, the altered concentration of AM in diabetes could indicate a certain interaction between AM induction and vascular function. Hence, the induction of vascular AM can be a new target of therapeutic approach to diabetic complications. Copyright © 2001 John Wiley & Sons, Ltd. [source] 7-Ketocholesterol-induced apoptosisFEBS JOURNAL, Issue 12 2005Involvement of several pro-apoptotic but also anti-apoptotic calcium-dependent transduction pathways Oxysterols, and particularly 7-ketocholesterol, appear to be strongly involved in the physiopathology of atherosclerosis. These molecules are suspected to be cytotoxic to the cells of the vascular wall and monocytes/macrophages, particularly by inducing apoptosis. Previous studies have demonstrated that 7-ketocholesterol-induced apoptosis is triggered by a sustained increase of cytosolic-free Ca2+, which elicits the mitochondrial pathway of apoptosis by activation of the calcium-dependent phosphatase calcineurin, leading to dephosphorylation of the ,BH3 only' protein BAD. However, thorough study of the results suggests that other pathways are implicated in 7-ketocholesterol-induced cytotoxicity. In this study, we demonstrate the involvement of two other calcium-dependent pathways during 7-ketocholesterol-induced apoptosis. The activation of the MEK,ERK pathway by the calcium-dependent tyrosine kinase PYK 2, a survival pathway which delays apoptosis as shown by the use of the MEK inhibitor U0126, and a pathway involving another pro-apoptotic BH3 only protein, Bim. Indeed, 7-ketocholesterol treatment of human monocytic THP-1 cells induces the release of Bim-LC8 from the microtubule-associated dynein motor complex, and its association with Bcl-2. Therefore, it appears that 7-ketocholesterol-induced apoptosis is a complex phenomenon resulting from calcium-dependent activation of several pro-apoptotic pathways and also one survival pathway. [source] The role of calcium in apoptosis induced by 7,-hydroxycholesterol and cholesterol-5,,6,-epoxideJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 5 2009Sinéad Lordan Abstract Oxysterols, such as 7,-hydroxy-cholesterol (7,-OH) and cholesterol-5,,6,-epoxide (,-epoxide), may have a central role in promoting atherogenesis. This is thought to be predominantly due to their ability to induce apoptosis in cells of the vascular wall and in monocytes/macrophages. Although there has been extensive research regarding the mechanisms through which oxysterols induce apoptosis, much remains to be clarified. Given that experimental evidence has long associated alterations of calcium (Ca2+) homeostasis to apoptotic cell death, the aim of the present study was to determine the influence of intracellular Ca2+ changes on apoptosis induced by 7,-OH and ,-epoxide. Ca2+ responses in differentiated U937 cells were assessed by epifluorescence video microscopy, using the ratiometric dye fura-2. Over 15-min exposure of differentiated U937 cells to 30 ,M of 7,-OH induced a slow but significant rise in fura-2 ratio. The Ca2+ channel blocker nifedipine and the chelating agent EGTA blocked the increase in cytoplasmic Ca2+. Moreover, dihydropyridine (DHP) binding sites identified with BODIPY-FLX-DHP were blocked following pretreatment with nifedipine, indicating that the influx of Ca2+ occurred through L-type channels. However, following long-term incubation with 7,-OH, elevated levels of cytoplasmic Ca2+ were not maintained and nifedipine did not provide protection against apoptotic cell death. Our results indicate that the increase in Ca2+ may be an initial trigger of 7,-OH,induced apoptosis, but following chronic exposure to the oxysterol, the influence of Ca2+ on apoptotic cell death appears to be less significant. In contrast, Ca2+ did not appear to be involved in ,-epoxide,induced apoptosis. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:324,332, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20295 [source] Activated ,2 macroglobulin induces matrix metalloproteinase 9 expression by low-density lipoprotein receptor-related protein 1 through MAPK-ERK1/2 and NF-,B activation in macrophage-derived cell linesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2010Leandro C. Cáceres Abstract Macrophages under certain stimuli induce matrix metalloproteinase 9 (MMP-9) expression and protein secretion through the activation of MAPK-ERK and NF-,B signaling pathways. Previously, we demonstrated that activated ,2 -macroglulin (,2M*) through the interaction with its receptor low-density lipoprotein receptor-related protein 1 (LRP1) induces macrophage proliferation mediated by the activation of MAPK-ERK1/2. In the present work, we examined whether ,2M*/LRP1interaction could induce the MMP-9 production in J774 and Raw264.7 macrophage-derived cell lines. It was shown that ,2M* promoted MMP-9 expression and protein secretion by LRP1 in both macrophage-derived cell lines, which was mediated by the activation of MAPK-ERK1/2 and NF-,B. Both intracellular signaling pathways activated by ,2M* were effectively blocked by calphostin-C, suggesting involvement of PKC. In addition, we demonstrate that ,2M* produced extracellular calcium influx via LRP1. However, when the intracellular calcium mobilization was inhibited by BAPTA-AM, the ,2M*-induced MAPK-ER1/2 activation was fully blocked in both macrophage cell lines. Finally, using specific pharmacological inhibitors for PKC, Mek1, and NF-,B, it was shown that the ,2M*-induced MMP-9 protein secretion was inhibited, indicating that the MMP production promoted by the ,2M*/LRP1 interaction required the activation of both signaling pathways. These findings may prove useful in the understanding of the macrophage LRP1 role in the vascular wall during atherogenic plaque progression. J. Cell. Biochem. 111: 607,617, 2010. © 2010 Wiley-Liss, Inc. [source] Hypoxia stimulates the autocrine regulation of migration of vascular smooth muscle cells via HIF-1,-dependent expression of thrombospondin-1JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2008Mayuko Osada-Oka Abstract The migration of vascular smooth muscle cells from the media to intima and their subsequent proliferation are critical causes of arterial wall thickening. In atherosclerotic lesions increases in the thickness of the vascular wall and the impairment of oxygen diffusion capacity result in the development of hypoxic lesions. We investigated the effect of hypoxia on the migration of human coronary artery smooth muscle cells (CASMCs) via HIF-1,-dependent expression of thrombospondin-1 (TSP-1). When the cells were cultured under hypoxic conditions, mRNA and protein levels of TSP-1, and mRNA levels of integrin ,3 were increased with the increase in HIF-1, protein. DNA synthesis and migration of the cells were stimulated under the conditions, and a neutralizing anti-TSP-1 antibody apparently suppressed the migration, but not DNA synthesis. The migration was also inhibited by RGD peptide that binds to integrin ,3. Furthermore, the migration was completely suppressed in HIF-1,-knockdown cells exposed to hypoxia, while it was significantly enhanced in HIF-1,-overexpressing cells. These results suggest that the hypoxia induces the migration of CASMCs, and that the migration is elicited by TSP-1 of which induction is fully dependent on the stabilization of HIF-1,, in autocrine regulation. Thus we suggest that HIF-1, plays an important role in the pathogenesis of atherosclerosis. J. Cell. Biochem. 104: 1918,1926, 2008. © 2008 Wiley-Liss, Inc. [source] Efficient estimation of three-dimensional curves and their derivatives by free-knot regression splines, applied to the analysis of inner carotid artery centrelinesJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES C (APPLIED STATISTICS), Issue 3 2009Laura M. Sangalli Summary., We deal with the problem of efficiently estimating a three-dimensional curve and its derivatives, starting from a discrete and noisy observation of the curve. This problem is now arising in many applicative contexts, thanks to the advent of devices that provide three-dimensional images and measures, such as three-dimensional scanners in medical diagnostics. Our research, in particular, stems from the need for accurate estimation of the curvature of an artery, from image reconstructions of three-dimensional angiographies. This need has emerged within the AneuRisk project, a scientific endeavour which aims to investigate the role of vessel morphology, blood fluid dynamics and biomechanical properties of the vascular wall, on the pathogenesis of cerebral aneurysms. We develop a regression technique that exploits free-knot splines in a novel setting, to estimate three-dimensional curves and their derivatives. We thoroughly compare this technique with a classical regression method, local polynomial smoothing, showing that three-dimensional free-knot regression splines yield more accurate and efficient estimates. [source] Progenitor cell trafficking in the vascular wallJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009M. HRISTOV Summary., Adult endothelial as well as smooth muscle progenitor cells are engaged in the complex pathophysiology of atherosclerosis including primary remodeling with development and progression of atherosclerotic plaques as well as secondary complications associated with ischemia, endothelial damage, neointimal growth and transplant arteriosclerosis. These adult vascular precursor cells correspond to similar embryonic stem cell-derived progeny and are primarily located in bone marrow and peripheral blood. Recently, specific investigation on their recruitment emerged as a novel fundamental in the pathogenesis of arterial remodeling, plaque stability and angiogenesis. This multifaceted process of mobilization and homing is regulated by numerous chemokines, adhesion molecules and growth factors that guide and control the trafficking of vascular progenitor cells to the arterial wall after injury or during ischemia. [source] Effect of Aging on the Structure and Function of Skeletal Muscle Microvascular NetworksMICROCIRCULATION, Issue 4 2006SHAWN E. BEARDEN ABSTRACT Humans are active creatures, yet physical activity and activity tolerance decline over the life span. One prevailing theme in the literature to account for a portion of the reduced activity tolerance with aging is the observation that the capacity to augment blood flow to skeletal muscle may be impaired with advancing age. This dysfunction may be due to adaptations in the structure or function of their microvascular networks, which collectively determine blood flow resistance. The intent of this review is to present the current knowledge of structure and function of microvascular networks from skeletal muscle with special regard to how these may adapt to, or persist through, the aging process. Skeletal muscles are supplied by an intricate branching network of arterioles and venules. The consistency of findings among available studies suggests that the overall arteriolar and venular network branching topology establishes early in development and varies little, if at all, over the life span. Microvascular networks are not a series of functionally isolated segmental branches. Rather, these networks transmit and communicate vasomotor signals along their lengths and among their branches. Current evidence suggests that aging is associated with a decrement in the capacity of upstream vessels to respond to downstream vasodilation and signals transmitted cell-to-cell along the vascular wall. [source] Carotid vascular remodelling in patients with autosomal dominant polycystic kidney diseaseNEPHROLOGY, Issue 1 2009SHU RONG SUMMARY Aim: To study carotid vascular wall remodelling in patients with autosomal dominant polycystic kidney disease (ADPKD) using integrated backscatter signal (IBS) analysis. Methods: Included in the study were: 60 ADPKD patients with preserved renal function, including 32 patient with hypertension and 28 with normotension; 25 patients with essential hypertension; and 30 healthy volunteers. Carotid intima-media thickness (IMT) was measured by 2-D conventional ultrasonography. Acoustic tissue characterization of the carotid wall was assessed by IBS analysis, and the percentage of regions considered as fibromatosis was calculated in all groups. Results: Carotid IMT in hypertensive ADPKD patients (0.8 ± 0.05 vs 0.68 ± 0.02 mm, P < 0.01 and 0.8 ± 0.05 vs 0.56 ± 0.04 mm, P < 0.01 respectively) and patients with essential hypertension (0.79 ± 0.03 vs 0.68 ± 0.02 mm, P < 0.01 and 0.79 ± 0.03 vs 0.56 ± 0.0 4 mm, P < 0.01 respectively) was significantly greater than that of normotensive patients and healthy subjects. Carotid IMT in normotensive ADPKD patients was also significantly greater than that in healthy subjects (0.68 ± 0.02 vs 0.56 ± 0.04 mm, P < 0.01). Calibrated IBS (C-IBS) in hypertensive ADPKD patients was significantly greater than that in patients with essential hypertension and normotensive ADPKD patients (,21.2 ± 1.51 dB vs ,23.1 ± 1.61 dB, P < 0.05; ,21.2 ± 1.51 dB vs ,24.5 ± 1.34 dB, P < 0.01). C-IBS in normotensive ADPKD patients was significantly greater than that in healthy subjects (,24.5 ± 1.34 dB vs ,26.2 ± 1.69 dB, P < 0.01). The percentage of regions that could be considered as fibromatosis in hypertensive ADPKD patients was significantly greater than that in patients with essential hypertension and normotensive ADPKD patients (30.0% vs 22.4%, P < 0.05; 30.0% vs 17.9%, P < 0.01). The percentage of regions that could be considered as fibromatosis in normotensive ADPKD patients was significantly greater than that in healthy subjects (15.2% vs 10.3%, P < 0.01). Conclusion: Carotid remodelling occurs in the early stage of ADPKD and can be aggravated by hypertension. Fibrosis contributes to the vascular rearrangement. [source] Oxygen infusions (hemoglobin-vesicles and albumin-hemes) based on nano-molecular sciences,POLYMERS FOR ADVANCED TECHNOLOGIES, Issue 2-3 2005Professor Eishun Tsuchida Abstract Since the discovery of a red-colored saline solution of a heme derivative that reversibly binds and releases oxygen (1983), significant efforts have been made to realize an oxygen infusion as a red cell substitute based on the sciences of both molecular assembling phenomena and macromolecular metal complexes. The authors have specified that hemoglobin (Hb)-vesicles (HbV) and recombinant human serum albumin-hemes (rHSA-heme) would be the best systems that meet the clinical requirements. (A) Hb is rigorously purified from outdated, donated red cells via pasteurization and ultrafiltration, to completely remove blood type antigen and pathogen. The HbV encapsulates thus purified concentrated Hb solution with a phospholipid bimolecular membrane (diameter, 250,nm,), and its solution properties can be adjusted comparable with blood. Surface modification of HbV with a water-soluble polymer ensures stable dispersion state and storage over a year at 20°C. In vivo tests have clarified the efficacy for extreme hemodilution and resuscitation from hemorrhagic shock, and safety in terms of biodistribution, metabolism in reticuloendothelial system (RES), clinical chemistry, blood coagulation, etc. The HbV does not induce vasoconstriction thus maintains blood flow and tissue oxygenation. (B) rHSA is now manufactured in Japan as a plasma-expander. The rHSA can incorporate eight heme derivatives (axial base substituted hemes) as oxygen binding sites, and the resulting rHSA-heme is a totally synthetic O2 -carrier. Hb binds endothelium-derived relaxation factor, NO, and induces vasoconstriction. The rHSA-heme binds NO as Hb does, however, it does not induce vasoconstriction due to its low pI (4.8) and the resulting low permeability across the vascular wall (1/100 of Hb). A 5%-albumin solution possesses a physiologic oncotic pressure. Therefore, to increase the O2 -transporting capacity, albumin dimer is effective. Albumin dimer can incorporate totally 16 hemes with a regulated oncotic pressure. The rHSA-heme is effective not only as a red cell substitute but also for oxygen therapeutics (e.g. oxygenation for tumor). Significant efforts have been made to produce HbV and rHSA-heme with a facility of Good Manufacturing Practice (GMP) standard, and to start preclinical and finally clinical trials. Copyright © 2005 John Wiley & Sons, Ltd. [source] An optimum method designed for 2-D DIGE analysis of human arterial intima and media layers isolated by laser microdissectionPROTEOMICS - CLINICAL APPLICATIONS, Issue 10 2009Fernando de la Cuesta Abstract The formation and progression of atherosclerotic lesions involve complex mechanisms which are still not fully understood. A variety of cell types from the distinct arterial layers are implicated in the whole process from lipid accumulation within the vascular wall to plaque development and final rupture. In the present work, we employ the combination of laser microdissection and pressure catapulting and 2-D DIGE saturation labeling to investigate the human intima and media sub-proteomes isolated from atherosclerotic (coronary and aorta) or non-atherosclerotic vessels (preatherosclerotic coronary arteries). Laser microdissection and pressure catapulting allows the specific isolation of regions of interest. In turn, DIGE saturation labeling overcomes the limitation of extensive microdissection times to recover the protein amount required to perform comparative 2-DE, particularly when dealing with tissue regions rich in myofilament proteins, which result in low protein recovery. The compatibility and optimum performance of both techniques were investigated in detail, paying special attention to tissue staining and protein solubilization. Since scarce amount of protein obtained from microdissected tissue made it impossible to directly perform protein identification from 2-DE spots by MS, we performed in-solution digestion followed by LC-MS/MS analysis of total protein extracts from intima and media in order to get an overall picture of protein composition. Proteins so identified confirm the nature of the isolated regions. Finally, similar spot resolution on 2-D DIGE gels was obtained for the different human artery types (coronary, aorta) and studied layers (intima, media), setting the basis for future clinical comparative studies. [source] Heparin Coating of Small-Caliber Decellularized Xenografts Reduces Macrophage Infiltration and Intimal HyperplasiaARTIFICIAL ORGANS, Issue 6 2009Wei-Wei Cai Abstract Small-caliber decellularized xenografts with surface heparin coating are known to reduce in vivo thrombogenicity. This study was performed to examine whether heparin coating on the small-caliber decellularized xenografts would reduce macrophage infiltration and intimal hyperplasia. In a rabbit model of bilateral carotid implantation, each of the animals (n = 18) received a heparin-coated decellularized xenograft from a canine carotid artery on one side and a nonheparin-coated one on the other side. These experiments were terminated respectively at 1 week (n = 6), 3 weeks (n = 6), and 12 weeks (n = 6). Results showed that, compared with the nonheparin-coated grafts, the heparin-coated grafts had significantly less macrophage infiltration 1 week after implantation, identified by the mouse antirabbit macrophage antibody (RAM11)-positive cells on the vascular wall, covering all the proximal, middle, and distal parts of the grafts (P < 0.01). Moreover, the heparin-coated grafts also showed less deposition of proliferation cell nuclear antigen (PCNA)-positive cells on the vascular wall, indicating less cell proliferation, which was significant not only at 1 week (P < 0.01) but also at 12 weeks (P < 0.01). Intimal hyperplasia, measured by the intimal : media (I : M) ratio, was found similar in both groups at 1 and 3 weeks. However, the I : M ratio was significantly lower in the heparin-coated group than in the nonheparin-coated group at 12 weeks, especially in the proximal anastomosis area (0.76 ± 0.12 vs. 0.345 ± 0.06, P < 0.01). Heparin coating of small-caliber decellularized xenografts is associated with an early reduction of macrophage infiltration and intimal hyperplasia in a rabbit model of bilateral carotid artery implantation for 12 weeks. Thus, heparin coating appears to deliver not only the antithrombogeneity but also the antiproliferative property for small-caliber decellularized xenografts. [source] Long-term streptozotocin-induced diabetes alters prostanoid production in rat aorta and mesenteric bedAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2006H. A. Peredo Summary 1 Vascular disease is a major cause of mortality and morbidity in chronic diabetes mellitus. 2 Prostanoids, metabolites of arachidonic acid, include vasoactive substances produced and released from the vascular wall. Alterations in prostanoid production have been reported in the vasculature of diabetic humans and experimental animals. 3 The aim of the present work was to study the influence of three different periods of long-term streptozotocin-induced diabetes, 30, 120 and 180 days in the production of prostanoids in the thoracic aorta and in the mesenteric vascular bed of the rat. The prostanoids released to the incubation medium by the tissues were extracted and measured by reversed-phase HPLC. 4 In the diabetic groups, body weight was reduced and glycaemia was increased when compared with the corresponding non-diabetic controls. 5 In the aorta, 30 days of diabetes did not modify the prostanoid release pattern, meanwhile 120 and 180 days of incubation decreased prostacyclin (PGI2) production. In the mesenteric bed, at 30 days the release of the vasodilators PGI2 and prostaglandin (PGE2) and the vasoconstrictor thromboxane (TXA2) was reduced. At 120 days the vasodilators were reduced and at 180 days such reduction was joined by an increase of the release of vasoconstrictor metabolites. 6 Thirty days of diabetes did not modify the PGI2/TXA2 ratio in the aorta or mesenteric bed. On the other hand, 120 and 180 days of diabetes reduced significantly the ratio when compared with the corresponding controls. 7 In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of diabetes on prostanoid production. The observed effects contribute to a displacement of the balance of prostanoid release in favour of the vasoconstrictor metabolites, a phenomenon that could be related to the vascular complications of diabetes mellitus. [source] Oral treatment and in vitro incubation with fructose modify vascular prostanoid production in the ratAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2006H. A. Peredo Summary 1 In the rat, a fructose-enriched diet induces hyperglycaemia, hypertriglyceridaemia, insulin resistance and hypertension; a model which resembles the human metabolic syndrome. 2 Prostanoids, metabolites of arachidonic acid, include vasoactive substances synthesized and released from the vascular wall that have been implicated in the increase of peripheral resistance, one of the mechanisms involved in the fructose-induced hypertension. 3 The aim of the present study was to: (i) analyse the effects of the in vitro incubation with fructose on the production and release of prostanoids in rat thoracic aorta and in rat mesenteric bed and (ii) compare the effects of incubation with those of the in vivo acute and chronic treatment of rats with fructose and with the combination of both in vivo and in vitro procedures. 4 Blood pressure, glycaemia and triglyceridaemia were significantly elevated in both 4- and 22-week fructose-treated groups. Meanwhile, body and heart weight as well as insulinaemia were similar between experimental animals and controls. 5 In aortae, 4 weeks of Fructose treatment did not modify the prostanoid pattern release, but in vitro incubation decreased prostacyclin (PGI2) production. However, after 22 weeks, fructose treatment and incubation exerted the same effect. 6 In mesenteric bed, after 4 weeks, the incubation and the combination of both procedures reduced the release of the vasodilators PGI2 and PGE2, while fructose treatment only diminished the PGE2 release. On the contrary, the production of the vasoconstrictor thromboxane A2 (TXA2) was enhanced by incubation and both the procedures. After 22 weeks, fructose treatment increased PGI2 release, while it was reduced by incubation. The combination of both did not modify this peripheral resistance when compared with controls. Finally, incubation of tissues from treated rats increased the release of the vasoconstrictors, PGF2, and TXA2. 7 In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of fructose on prostanoid production. This difference could be related to a more relevant role of resistance vessels in the regulation of peripheral resistance and consequently of blood pressure. The observed effects should contribute to a shift in the balance of the release of prostanoid in favour of vasoconstrictor metabolites. This phenomenon could be related to an increase in the peripheral resistance and the mild hypertension observed in the fructose-treated rats. [source] Calcium-activated potassium channels and endothelial dysfunction: therapeutic options?BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2009Michel Félétou The three subtypes of calcium-activated potassium channels (KCa) of large, intermediate and small conductance (BKCa, IKCa and SKCa) are present in the vascular wall. In healthy arteries, BKCa channels are preferentially expressed in vascular smooth muscle cells, while IKCa and SKCa are preferentially located in endothelial cells. The activation of endothelial IKCa and SKCa contributes to nitric oxide (NO) generation and is required to elicit endothelium-dependent hyperpolarizations. In the latter responses, the hyperpolarization of the smooth muscle cells is evoked either via electrical coupling through myo-endothelial gap junctions or by potassium ions, which by accumulating in the intercellular space activate the inwardly rectifying potassium channel Kir2.1 and/or the Na+/K+ -ATPase. Additionally, endothelium-derived factors such as cytochrome P450-derived epoxyeicosatrienoic acids and under some circumstances NO, prostacyclin, lipoxygenase products and hydrogen peroxide (H2O2) hyperpolarize and relax the underlying smooth muscle cells by activating BKCa. In contrast, cytochrome P450-derived 20-hydroxyeicosatetraenoic acid and various endothelium-derived contracting factors inhibit BKCa. Aging and cardiovascular diseases are associated with endothelial dysfunctions that can involve a decrease in NO bioavailability, alterations of EDHF-mediated responses and/or enhanced production of endothelium-derived contracting factors. Because potassium channels are involved in these endothelium-dependent responses, activation of endothelial and/or smooth muscle KCa could prevent the occurrence of endothelial dysfunction. Therefore, direct activators of these potassium channels or compounds that regulate their activity or their expression may be of some therapeutic interest. Conversely, blockers of IKCa may prevent restenosis and that of BKCa channels sepsis-dependent hypotension. Mandarin translation of abstract [source] Bruch's membrane and the vascular intima: is there a common basis for age-related changes and disease?CLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 5 2005Sobha Sivaprasad FRCS Abstract Several clinical and epidemiological studies have concurrently illuminated established cardiovascular risk factors in age-related macular degeneration (AMD), raising the possibility that cardiovascular disease and AMD may share a similar pathogenic process. The vascular intima and the Bruch's membrane share several age-related changes and are the seat of many common molecules. Diseases of these structures may represent parallel responses to the tissue injury induced by multiple intercalated factors such as genetic variations, oxidative stress, inappropriately directed immune response or inflammatory disease complex. However, there are marked differences in the age-related changes in these two structures. The strategic location of the Bruch's membrane between the retinal pigment epithelium and the choriocapillaris can at least partially explain the differential susceptibility of AMD to cardiovascular risk factors. Unlike the vascular wall that is exposed to changes from the endothelium, the Bruch's membrane is subject to changes from both the endothelium (choriocapillaris) and epithelium (retinal pigment epithelium). Moreover, although both the vascular wall and Bruch's membrane become lipid laden with age, the lipid composition is characteristically different. This review examines the morphological and biochemical alterations in the senescent Bruch's membrane and its analogy to the vascular wall to evaluate the concurrence of atherosclerosis and AMD. [source] RALOXIFENE, TAMOXIFEN AND VASCULAR TONECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2007Fung Ping Leung SUMMARY 1Oestrogen deficiency causes progressive reduction in endothelial function. Despite the benefits of hormone-replacement therapy (HRT) evident in earlier epidemiological studies, recent randomized trials of HRT for the prevention of heart disease found no overall benefit. Instead, HRT users had higher incidences of stroke and heart attack. Most women discontinue HRT because of its many side-effects and/or the increased risk of breast and uterine cancer. This has contributed to the development of selective oestrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, as alternative oestrogenic agents. 2A SERM is a molecule that binds with high affinity to oestrogen receptors but has tissue-specific effects distinct from oestrogen, acting as an oestrogen agonist in some tissues and as an antagonist in others. Clinical and animal studies suggest multiple cardiovascular effects of SERMs. For example, raloxifene lowers serum levels of cholesterol and homocysteine, attenuates oxidation of low-density lipoprotein, inhibits endothelial,leucocyte interaction, improves endothelial function and reduces vascular smooth muscle tone. 3Available evidence suggests that raloxifene and tamoxifen are capable of acting directly on both endothelial cells and the underlying vascular smooth muscle cells and cause a multitude of favourable modifications of the vascular wall, which jointly contribute to improved local blood flow. The outcome of the Raloxifene Use for the Heart (RUTH) trial will determine whether raloxifene, currently approved for the treatment of post-menopausal osteoporosis, could substitute for HRT in alleviating cardiovascular symptoms in post-menopausal women. [source] GENETIC INFLUENCES ON THE ARTERIAL WALLCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2007Bronwyn Kingwell SUMMARY 1Arterial stiffness, which has independent predictive value for cardiovascular events, seems to have a genetic component, largely independent of the influence of blood pressure and other cardiovascular risk factors. 2In animal models of essential hypertension (stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats), structural modifications of the arterial wall include an increase in the number of elastin,smooth muscle cell connections and smaller fenestrations of the internal elastic lamina, possibility leading to redistribution of the mechanical load towards elastic materials. These modifications may give rise to mechanisms explaining why changes in arterial wall material accompanying wall hypertrophy in these animals are not associated with an increase in arterial stiffness. 3In monogenic connective tissue diseases (Marfan, Williams and Ehlers,Danlos syndromes) and the corresponding animal models, precise characterization of the arterial phenotype makes it possible to determine the influence of abnormal, genetically determined, wall components on arterial stiffness. 4Such studies have highlighted the role of extracellular matrix signalling in the vascular wall and have shown that elastin and collagen not only display elasticity or rigidity, but are also involved in the control of smooth muscle cell function. 5These data provide strong evidence that arterial stiffness is affected by the amount and density of stiff wall material and the spatial organization of that material. [source] Correction of protein kinase C activity and macrophage migration in peripheral nerve by pioglitazone, peroxisome proliferator activated-,-ligand, in insulin-deficient diabetic ratsJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Shin-Ichiro Yamagishi Abstract Pioglitazone, one of thiazolidinediones, a peroxisome proliferator-activated receptor (PPAR)-, ligand, is known to have beneficial effects on macrovascular complications in diabetes, but the effect on diabetic neuropathy is not well addressed. We demonstrated the expression of PPAR-, in Schwann cells and vascular walls in peripheral nerve and then evaluated the effect of pioglitazone treatment for 12 weeks (10 mg/kg/day, orally) on neuropathy in streptozotocin-diabetic rats. At end, pioglitazone treatment improved nerve conduction delay in diabetic rats without affecting the expression of PPAR-,. Diabetic rats showed suppressed protein kinase C (PKC) activity of endoneurial membrane fraction with decreased expression of PKC-,. These alterations were normalized in the treated group. Enhanced expression of phosphorylated extracellular signal-regulated kinase detected in diabetic rats was inhibited by the treatment. Increased numbers of macrophages positive for ED-1 and 8-hydroxydeoxyguanosine-positive Schwann cells in diabetic rats were also corrected by the treatment. Pioglitazone lowered blood lipid levels of diabetic rats, but blood glucose and nerve sorbitol levels were not affected by the treatment. In conclusion, our study showed that pioglitazone was beneficial for experimental diabetic neuropathy via correction of impaired PKC pathway and proinflammatory process, independent of polyol pathway. [source] Clinical, histological and immunohistochemical findings in oral Kaposi's sarcoma in a series of Mexican AIDS patients.JOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2009Comparative study Background:, The origin of spindle cells (SC) in oral Kaposi's sarcoma (OKS) is still an intriguing aspect. Thus the aim of the present study was to compare the clinical, histological and immunohistochemical characteristics of OKS and oral pyogenic granuloma (OPG), in order to contribute to the knowledge of the cells involved in Kaposi,s sarcoma pathogenesis. Methods:, In this retrospective, observational and comparative study, 39 OKS and 30 OPG cases were included. Immunohistochemical studies were performed for vimentin, ,SMA, desmin, C-kit, CD34, D2-40 and LANA-1 [human herpesvirus-8(HHV-8)]. Statistical comparisons were done using the chi-square and Wilcoxon,Mann,Whitney rank sum tests. Results:, Fourteen (35.9%) OKS cases also affected the skin, and 83.8% involved the palate. All OKS and OPG were positive for vimentin and CD34. OKS samples were positive for ,SMA, and 25.6% expressed C-kit. All OKS cases were positive for HHV-8, and the number of positive cells increased significantly from early,/,intermediate to late histological stage. D2-40 was expressed in the cellular component and vascular walls of all OKS cases, but it was negative in OPG. HHV-8 expression was increased in late histological stages of OKS lesions. Conclusions:, The expression of D2-40 marker in the vascular walls and SC supports the view of a lymphatic differentiation in neoplastic cells of OKS. Desmin, ,SMA, D2-40, C-kit and HHV-8 were the main markers differently expressed in OKS and OPG. [source] Resveratrol: Preventing properties against vascular alterations and ageingMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 5 2005Dominique Delmas Abstract Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects. We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activites by resveratrol can lead to a prevention of vascular diseases. [source] | |||||||||||||||||||||||||||||||