Arterial Blood Vessels Research Articles

Correlation of waist-hip ratio, vascular elasticity and adiposity

Objective To explore the influence of elderly waist-hip ratio (WHpR) on adiposity and vascular elasticity. Methods A total of 120 healthy middle aged and elderly people aged 40-60 years old were selected between February, 2015 and December, 2015. A number of 60 patients with normal ratio of WHpR were treated as a control group, while another 60 patients with higher ratio of WHpR as study group. Adiposity, arterial blood vessel elasticity, blood pressure, blood fat and blood glucose of two groups were compared. Results Normal rate of body fat and arterial blood vessel of the study group were lower than those of the control group. Adiposity, pulse wave velocity(PWV), body mass index of the study group were significantly higher than those of the control group. Systolic blood pressure, diastolic blood pressure, pulse pressure, blood glucose, uric acid, three acyl glycerin, total cholesterol, low-density lipoprotein cholesterol of the study group were higher than those of the control group, high density lipoprotein cholesterol was lower than that of the control group(P<0.05). WHpR was positively associated with Adiposity, degree of elastic stiffness of blood vessels and body mass index (r=0.135, P=0.011; r=0.189, P=0.013; r=0.146, P=0.014). Degree of elastic stiffness of blood vessels was positively related with WHpR, adiposity, body mass index (r=0.189, P=0.013; r=0.123, P=0.009; r=0.097, P=0.021). Conclusions WHpR can be used as an early evaluation index of Adiposity and blood vessel elasticity for middle aged and elderly people. Key words: Waist-hip ratio; Adiposity; Blood vessel elasticity; Pulse wave velocity

P46 Oxidisedoxidized LDL and LOX-1 scavenger receptor regulation of pro-atherogenic signal transduction

Atherosclerosis is a chronic inflammatory disease characterised by lipid-laden lesions within arterial blood vessel walls. Inflammation is a central driver in atherosclerosis and is regulated by different signal transduction pathways in vascular cells and tissues. A major risk factor that promotes atherosclerosis is elevated oxidised low-density lipoprotein (oxLDL) particles, which is recognised by lectin-like oxLDL scavenger receptor 1 (LOX-1). LOX-1 is implicated in promoting atherosclerosis but the mechanism of action is unclear. To assess how LOX-1 signal transduction promotes disease outcomes, we used genetically engineered cell and animal models. We made a tetracycline-inducible endothelial cell line that expresses tagged wild-type human LOX-1. Stimulation of LOX-1-expressing endothelial cells with oxLDL causes increased signal transduction consistent with a role for LOX-1 in promoting inflammation and apoptosis. OxLDL binding stimulates LOX-1 endocytosis; however, LOX-1 undergoes efficient recycling from endosome-to-plasma membrane under stimulated and non-stimulated conditions. Although LOX-1-null transgenic mice displayed no obvious defects, LOX-1/ApoE-double null transgenic mice showed ~30% increase in atherosclerosis incidence compared to controls. Tissue analysis indicates that the presence of LOX-1 suppresses ERK1/2, p38 MAPK and NF-κB signal transduction. LOX-1 is thus an important link between dietary fats, pro-inflammatory signal transduction and atherosclerosis.

Effects of pomegranate extract on blood flow and vessel diameter after high-intensity exercise in young, healthy adults

The effects of pomegranate extract (PE) supplementation were evaluated on high-intensity exercise performance, blood flow, vessel diameter, oxygen saturation (SPO2), heart rate (HR), and blood pressure (BP). In a randomized, crossover design, nineteen recreationally resistance-trained participants were randomly assigned to PE (1000 mg) or placebo (PL), which were consumed 30 min prior to a repeated sprint ability (RSA) test and repetitions to fatigue (RTF) on bench and leg press. The RSA consisted of ten six-second sprints on a friction-loaded cycle ergometer with 30 s recovery. Brachial artery blood flow and vessel diameter were assessed by ultrasound. Blood flow, vessel diameter, SPO2, HR, and BP were assessed at baseline, 30 min post ingestion, immediately post exercise (IPost), and 30 min post exercise (30minPost). With PE, blood flow significantly increased IPost RSA (mean difference = 18.49 mL min−1; P < .05), and IPost and 30minPost RTF (P < .05) according to confidence intervals (CI). Vessel diameter increased significantly 30minPost RSA according to CI and resulted in a significant interaction IPost and 30minPost RTF (P < .05). With PE, according to CI, average and peak power output increased significantly in sprint 5 of the RSA (P < .05). There was no significant difference between PE and PL for bench (P = .25) or leg press (P = .15) repetitions. Acute PE supplementation enhanced vessel diameter and blood flow, suggesting possible exercise performance enhancement from increased delivery of substrates and oxygen. The acute timing and capsule form of PE may be advantageous to athletic populations due to ergogenic effects, taste, and convenience.

S100A6 Regulates Endothelial Cell Cycle Progression by Attenuating Antiproliferative Signal Transducers and Activators of Transcription 1 Signaling.

S100A6, a member of the S100 protein family, has been described as relevant for cell cycle entry and progression in endothelial cells. The molecular mechanism conferring S100A6's proliferative actions, however, remained elusive. Originating from the clinically relevant observation of enhanced S100A6 protein expression in proliferating endothelial cells in remodeling coronary and carotid arteries, our study unveiled S100A6 as a suppressor of antiproliferative signal transducers and activators of transcription 1 signaling. Discovery of the molecular liaison was enabled by combining gene expression time series analysis with bioinformatic pathway modeling in S100A6-silenced human endothelial cells stimulated with vascular endothelial growth factor A. This unbiased approach led to successful identification and experimental validation of interferon-inducible transmembrane protein 1 and protein inhibitors of activated signal transducers and activators of transcription as key components of the link between S100A6 and signal transducers and activators of transcription 1. Given the important role of coordinated endothelial cell cycle activity for integrity and reconstitution of the inner lining of arterial blood vessels in health and disease, signal transducers and activators of transcription 1 suppression by S100A6 may represent a promising therapeutic target to facilitate reendothelialization in damaged vessels.

Stochastic cycle selection in active flow networks

Active biological flow networks pervade nature and span a wide range of scales, from arterial blood vessels and bronchial mucus transport in humans to bacterial flow through porous media or plasmodial shuttle streaming in slime molds. Despite their ubiquity, little is known about the self-organization principles that govern flow statistics in such nonequilibrium networks. Here we connect concepts from lattice field theory, graph theory, and transition rate theory to understand how topology controls dynamics in a generic model for actively driven flow on a network. Our combined theoretical and numerical analysis identifies symmetry-based rules that make it possible to classify and predict the selection statistics of complex flow cycles from the network topology. The conceptual framework developed here is applicable to a broad class of biological and nonbiological far-from-equilibrium networks, including actively controlled information flows, and establishes a correspondence between active flow networks and generalized ice-type models.

Análisis dimensional del comportamiento hiperelástico del tubo arterial bajo un estado multiaxial de tensiones

A study of the behavior of the arterial blood vessel was performed by resorting to the mechanics of hyperelastic solids, for this is a currently well-established means to understanding a number of phenomena of concern among physicians and biomedical engineers. As regards this organ, it was modelled as a thick walled cylindrical vessel where the material energy function comprised the characterization of microstructural features of the tissue, such as anisotropy and fiber orientation dispersion. The static equilibrium problem for implementing this model represented the adventitia and media layers of the arterial wall, while its solution was simple thanks to assuming an axisymmetric deformation pattern. It is found that the fiber orientation factor along with the other dimensionless quantities of the same order of magnitude had the most influence on the arterial blood vessel radial stiffness. These results were processed using dimensional groups, thereby facilitating interpretation in the light of the many parameters that the whole model considers.

Longitudinal live imaging of retinal α-synuclein::GFP deposits in a transgenic mouse model of Parkinson's Disease/Dementia with Lewy Bodies.

Abnormal α-synuclein (α-syn) accumulation in the CNS may underlie neuronal cell and synaptic dysfunction leading to motor and cognitive deficits in synucleinopathies including Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Multiple groups demonstrated α-syn accumulation in CNS accessory structures, including the eyes and olfactory terminals, as well as in peripheral organs of Parkinsonian patients. Retinal imaging studies of mice overexpressing fused α-syn::GFP were conducted to evaluate the presence and progression of retinal pathology in a PD/DLB transgenic mouse model. Bright-field image retinal maps and fluorescent images were acquired at 1-month intervals for 3 months. Retinal imaging revealed the accumulation of GFP-tagged α-syn in retinal ganglion cell layer and in the edges of arterial blood vessels in the transgenic mice. Double labeling studies confirmed that the α-syn::GFP-positive cells were retinal ganglion cells containing α-syn. Accumulation of α-syn persisted in the same cells and increased with age. Accumulation of α-syn::GFP was reduced by immunization with single chain antibodies against α-syn. In conclusion, longitudinal live imaging of the retina in the PDGF-α-syn::GFP mice might represent a useful, non-invasive tool to monitor the fate of α-syn accumulation in the CNS and to evaluate the therapeutic effects of compounds targeting α-syn.

Systematic analysis of the molecular mechanism underlying atherosclerosis using a text mining approach.

BackgroundAtherosclerosis is one of the common health threats all over the world. It is a complex heritable disease that affects arterial blood vessels. Chronic inflammatory response plays an important role in atherogenesis. There has been little success in fully identifying functionally important genes in the pathogenesis of atherosclerosis.ResultsIn the present study, we performed a systematic analysis of atherosclerosis-related genes using text mining. We identified a total of 1312 genes. Gene ontology (GO) analysis revealed that a total of 35 terms exhibited significance (p < 0.05) as overrepresented terms, indicating that atherosclerosis invokes many genes with a wide range of different functions. Pathway analysis demonstrated that the most highly enriched pathway is the Toll-like receptor signaling pathway. Finally, through gene network analysis, we prioritized 48 genes using the hub gene method.ConclusionsOur study provides a valuable resource for the in-depth understanding of the mechanism underlying atherosclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0075-1) contains supplementary material, which is available to authorized users.

Abstract 378: Cytochrome b5 Reductase 3 Regulates Vascular Smooth Muscle Phenotypic Switching

Contractile vascular smooth muscle cells (VSMC) play a key role in the regulation of arterial blood vessel tone and cardiovascular health. However, in many vascular diseases, VSMCs undergo a phenotypic switch from a contractile state to a synthetic phenotype, where loss of the contractile markers myosin heavy chain 11 (Myh11), smooth muscle alpha actin (ACTA2) and transgelin (SM22) are observed and proliferation is increased. Recent evidence from our lab demonstrates that cytochrome b5 reductase 3 (Cyb5R3) regulates the redox state of soluble guanylate cyclase to control cGMP levels in VSMCs. Because cGMP modulates protein kinase G activity, a critical kinase that maintains VSMCs in a contractile state, we tested the hypothesis that Cyb5R3 is critical for maintenance of the contractile phenotype. To test this hypothesis, we transduced primary rat aortic smooth muscle cells with non-targeting (NT) or Cyb5R3 shRNA followed by serum starvation for 24, 48, and 72 hours to induce phenotypic switching. After each time point, mRNA measurements of Cyb5R3, Myh11, ACTA2, and SM22 were conducted using RT-PCR. In NT shRNA transduced VSMCs, we observed a significant increase in Cyb5R3, Myh11, ACTA2, and SM22 mRNA, but not in Cyb5R3 knockdown VSMCs. Next, we conducted proliferation studies by serum starving NT shRNA and Cyb5R3 shRNA treated VSMCs for 24 hours followed by stimulation of platelet growth factor BB (PDGF-BB, 40 ng/mL). After 24 hours of PDGF-BB treatment, Cyb5R3 deficient cells showed augmented proliferation compared to control cells measured by 3 H-thymidine incorporation. Together, our data suggest that Cyb5R3 is essential for VSMC phenotypic switching and proliferation, which may unravel a new therapeutic target for treating individuals with cardiovascular disease.

Pterostilbene, a novel natural plant conduct, inhibits high fat-induced atherosclerosis inflammation via NF-κB signaling pathway in Toll-like receptor 5 (TLR5) deficient mice.

Atherosclerosis is a specific form of an artery wall thickens, a syndrome affecting arterial blood vessels due to a chronic inflammatory response in the walls of arteries, which is promoted by fat accumulation. Toll-like receptors (TLRs) play prominent roles in inflammatory responses. And TLR5 is overexpressed in several diseases. Here in our study, we investigated the effect of TLR5 in high fat-induced atherosclerosis via NF-κB signaling pathway modulating pro-inflammatory cytokines releasing. Our results found that high fat induced atherosclerosis in wild type mice with fat accumulation and inflammatory response through NF-κB activation. Contrastly, TLR5 knockout mice displayed lower fat accumulation and ameliorated inflammation after high fat feeding with NF-κB inactivation. In addition, pterostilbene, as a natural dimethyl ether derivative of resveratrol mainly from blueberries, has diverse pharmacological activities, especially anti-inflammation. Our study also found that pterostilbene displayed inhibited role in suppressing inflammatory response through inactivating NF-κB signaling pathway regulated by TLR5 down-regulation in high fat-induced mice. Moreover, in vitro experiments of vascular smooth muscle cells (VSMCs) challenged with LPS or TNF-α, further indicated that NF-κB was involved in atherosclerosis progression, leading to high secretion of pro-inflammatory cytokines. However, VSMCs from TLR5 deficient mice inhibited phosphorylated levels of NF-κB signalilng pathway, finally resulting in down-regulation of inflammatory cytokines. Notably, pterostilbene also displayed suppressed role in inflammatory response via NF-κB inactivity in LPS or TNF-α-induced VSMCs by decreasing TLR5 expression. The results above indicated a novel therapeutic strategy of pterostilbene to protect against atherosclerosis via TLR5 regulation for clinic treatment in the future.

388 A novel Abcc6 knockout rat model highlights the role of PPi in the pathogenesis of ectopic mineralization process in PXE

388 A novel Abcc6 knockout rat model highlights the role of PPi in the pathogenesis of ectopic mineralization process in PXE Q Li, K van de Wetering, J Kingman, JP Sundberg and J Uitto 1 Thomas Jefferson University, Philadelphia, PA, 2 Netherlands Cancer Institute, Amsterdam, Netherlands and 3 The Jackson Laboratory, Bar Harbor, ME Pseudoxanthoma elasticum (PXE) is characterized by systemic connective tissue mineralization caused by loss-of-function mutations in the ABCC6 gene. The currently available Abcc6 mice represent a useful model system to study PXE pathophysiology and to explore potential treatment modalities. Abcc6 rats would, however, provide a more suitable model for metabolic studies and specifically unravel the role of PPi and Pi homeostasis in PXE. We have therefore generated Abcc6 rats using zinc finger nuclease (ZFN), targeting the first coding exon of Abcc6. Five germline transmission competent rats were identified that harbored deletions ranging from 10 to 23 bp surrounding the ZFN target site. These mutations were predicted to cause out-of-frame translation and induce a premature stop codon. Immunostaining of liver sections using a rat ABCC6 specific antibody showed plasma membrane expression in basolateral surface of hepatocytes in wild type rats and complete absence in the homozygous mutant rats. As a consequence of ABCC6 deficiency, complete necropsy of three mutant lines demonstrated ectopic mineralization in the muzzle skin, eyes, and arterial blood vessels in the knockout rats, features mimicking human PXE. Mineralization in the dermal sheath of vibrissae was also monitored by small animal CT scanning, which allows noninvasive evaluation of the mineralization process. Similar to human PXE patients, clinical chemistry did not reveal differences in serum calcium and phosphorus levels between wild type and Abcc6 rats. However, plasma PPi level was significantly reduced (<60%) in the Abcc6 rats as compared to wild type rats, leading to a significantly lower PPi/Pi ratio. Since PPi is physiologically a potent antimineralization factor, the results highlight the role of PPi in the context of the PPi/Pi ratio in the novel Abcc6 rat model due to loss-of-function of ABCC6, leading to ectopic mineralization in PXE. 389 Pirfenidone inhibits RDEB fibrosis and scarring J Cogan, K Yim, Y Hou, L Chao, V Gor, D Woodley and M Chen Dermatology, University of Southern California, Los Angeles, CA Patients with recessive dystrophic epidermolysis bullosa (RDEB) develop multiple skin wounds that heal with extensive scarring, contractures and mitten deformities. RDEB patients display increased pro-fibrotic TGF-b signaling, a distinct pro-fibrotic gene expression profile and elevated inflammation genes. So far, no specific pharmacological treatment is available for RDEB fibrosis. Among promising anti-fibrotic molecules, pirfenidone (PFD) has shown anti-fibrotic and anti-inflammatory activity in animal and cell models, and it is already being used clinically for the treatment of idiopathic pulmonary fibrosis. In this study, we evaluated the feasibility of using PFD to inhibit RDEB fibrosis using fibroblasts from RDEB patients and a RDEB mouse model. RDEB fibroblasts treated with PFD demonstrated reduced expression of multiple fibrosis markers [collagen I, connective tissue growth factor (CTGF), alpha smooth muscle actin (a-SMA), periostin, and tenascin C] by immunoblot analysis. By RT-PCR, PFD also reduced mRNA levels for fibrosis genes [tenascin-C, CTGF, periostin, TGF-b2, and aSMA] as well as IL-6, an inflammation gene known to stimulate fibrosis. In addition, PFD reduced the levels of pro-fibrogenic TGF-b in the media of RDEB fibroblasts as assessed by ELISA. Furthermore, PFD also reversed the characteristic RDEB cellular phenotype of collagen lattice hypercontractability. Lastly, using a RDEB mouse model featuring nail dystrophy and mitten deformities, PFD administered once daily subcutaneously for 4 weeks attenuated the onset of RDEB-associated fibrosis including mitten deformities and nail loss. It reduced in the skin of RDEB mice, their intrinsically elevated fibrosis markers [periostin, aSMA, fibronectin, collagen 1 and tenascin C] and pro-fibrogenic TGF-b and its downstream signaling [phospho-Smad2/3]. PFD also significantly reduced the number of cd11b-positive inflammatory cells in RDEB mice. These data demonstrate that PFD may be a non-invasive, safe and novel therapy for reducing RDEB fibrosis and scarring and improving the quality of life of RDEB patients.

Distinct bone marrow blood vessels differentially regulate haematopoiesis.

Bone marrow (BM) endothelial cells (BMECs) form a network of blood vessels (BVs) which regulate both leukocyte trafficking and hematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles and if these events occur at the same vascular site. We found that BM stem cell maintenance and leukocyte trafficking are regulated by distinct BV types with different permeability properties. Less permeable arterial BVs maintain HSCs in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the BM. A functional consequence of high BVs permeability is that exposure to blood plasma increases BM HSPC ROS levels, augmenting their migration capacity while compromising their long term repopulation and survival potential. These findings may have relevance for clinical hematopoietic stem cell transplantation and mobilization protocols.

Blood Flow Modelling of Linear and Sequential Bypass Coronal Vessels of the Heart

The paper presents results of blood flow parameters numerical simulation in the coronal vessels of the left coronary artery. Described mathematical model characterizing the hemodynamics of the coronary artery blood vessels allows the simulation of blood flow parameters changes in the coronal vessels subjected to bypass surgery. On the basis of this model blood flow parameters of linear and sequential bypasses types were calculated and compared.

Mathematical analysis of the effects of valvular regurgitation on the pumping efficacy of continuous and pulsatile left ventricular assist devices

BackgroundA left ventricular assist device (LVAD) is normally contraindicated in significant aortic regurgitation (AR) and requires intraoperative valve repair or exclusion. Nevertheless, AR can coexist with an LVAD, so a valid question when asked might still be of clinical significance. The purpose of this study is to analyze the effects of valve regurgitation on the pumping efficacy of continuous and pulsatile LVADs with a computational method. MethodsA cardiovascular model was developed based on the Windkessel model, which reflects the hemodynamic flow resistance and the blood wall elasticity. Using the Windkessel model, important cardiovascular components, such as the right atrium, right ventricle, pulmonary artery, pulmonary vein, left atrium (LA), left ventricle (LV), aorta, and branching blood vessels, were expressed. ResultsIn the case of AR, continuous and pulsatile LVADs improved cardiac output and reduced mechanical load slightly. In the case of mitral regurgitation, the LVADs improved cardiac output (cardiac outputs were about 5 L/min regardless of the severity of regurgitation) and reduced afterload significantly. ConclusionAR reduced both continuous and pulsatile LVAD function significantly while mitral regurgitation did not affect their pumping efficacy.

Patients After Splenectomy: Old Risks and New Perspectives.

The risks that arise after splenectomy can be divided in infectious and non-infectious. The link between splenectomy and these hazards remains partially unknown. Host defense against infection is altered after splenectomy and such individuals develop sepsis more easily and the infection has a fulminant course. Splenectomy is also a potential risk factor for several vascular complications that result from partial or total obstruction of an arterial or venous blood vessel. Furthermore, pulmonary hypertensioncan be a severe and sometimes fatal complication following splenectomy. Some authors also consider that malignancies, diabetes mellitus and acute pancreatitis are non-infectious complications after splenectomy. The most feared complication for splenectomized patients remains sepsis. The pathophysiology of sepsis is still controversial. Death in sepsis can occur due to either hyper-inflammation or immune paralysis. Multiple experimental evidences link cellular and viral microRNAs with sepsis. We presume that miRNAs are also associated with the immunosuppression of the asplenic patients which leads to the high risk of deadly sepsis. Studying the expression level of circulating miRNAs in asplenic patients could help us better understand the postsplenectomy immunosuppression and develop new diagnostic and therapeutic tools.

Safety and Effectiveness of a Circumferential Clip-Based Vascular Closure Device for Hemostasis in Off-Label Applications: Comparison with Standard Applications

을 천자 후 StarClose를 사용한 경우와 6 Fr 이하 크기의 동맥 Purpose: We investigated the efficacy and safety of a circumferential nitinol clip based arterial closure device following arteriotomy, especially in off-label applications. Materials and Methods: Consecutive patients who underwent the procedure with arteriotomy from January 2011 to February 2014 were included in this study. We defined standard use as the use of StarClose for retrograde puncture of the common femoral artery (CFA) and off-label use as the use of StarClose for retrograde puncture of the superficial femoral artery (SFA), antegrade puncture of the CFA or SFA, puncture of the brachial artery or puncture of the vascular graft. The procedures performed included percutaneous transluminal angioplasty and thrombolysis. Technical success was defined as complete hemostasis achieved within 3 minute after the closure. Complications, and laboratory findings associated with coagulation function, were also investigated. Results: There were 146 cases of standard applications and 111 cases of off-label applications. Technical success was achieved in all cases. The off-label group comprised the use of StarClose for retrograde puncture of the SFA (n = 19), antegrade puncture of the CFA or SFA (n = 74), brachial artery puncture (n = 5), larger sheath than 6 Fr (n = 7) and vascular graft puncture (n = 6). Minor complications were noted in both groups (standard group: 7.5%, off-label group: 2.7%). Conclusion: Off-label use of StarClose is safe and feasible. Index terms Vascular Closure Devices Femoral Artery Brachial Artery Blood Vessel Prosthesis Hemostatic Techniques

Construction of the arterial blood vessel model by layer-by-layer technique and its potential application for regenerative medicine

Construction of the arterial blood vessel model by layer-by-layer technique and its potential application for regenerative medicine

Suppression of proatherogenic leukocyte interactions by MCS-18 – Impact on advanced atherosclerosis in ApoE-deficient mice

ObjectiveAtherosclerosis is associated with chronic inflammatory responses of the arterial blood vessels. The previously observed protective effect of the MCS-18 substance against the initiation of atherosclerosis in a murine model was explained by its pronounced anti-inflammatory activity. Here, we investigated its impact on murine plaque progression in advanced atherosclerosis and on proatherogenic processes. Approach & ResultsApoE-deficient mice were fed a high-fat diet for 12 weeks to induce atherosclerosis, followed by normal chow and intraperitoneal injections of either MCS-18 (500 μg, n = 10) or saline (n = 10) twice a week for another 12 weeks. Plaque size was reduced in MCS-18 treated mice compared to controls (p = 0.001), which was associated with a reduced size of the lipid core (p = 0.01). There was a decrease in apoptotic cells (p = 0.02), endothelial ICAM-1 expression (p < 0.001), and macrophage density (p = 0.01) in the MCS-18 group. In addition, human and murine dendritic cells (DCs) and human umbilical vein endothelial cells (HUVECs) were treated with MCS-18 (50–200 μg/ml) to analyze cell migration and adhesion under flow conditions. MCS-18 reduced human (p = 0.01) and murine (p = 0.006) DC migration. Furthermore, adhesion of MCS-18-treated DCs to a HUVEC monolayer was decreased (p < 0.001). Compared to controls, CD209 (p < 0.001) and CCR7 (p = 0.003) expression was decreased in MCS-18-treated DCs, while in HUVECs lower levels of ICAM-1 (p < 0.001) and of phosphorylated NF-κB-p65 (p = 0.002) were observed. Blocking of ICAM-1 reduced DC adhesion (p < 0.001). ConclusionsMCS-18 exhibits interesting therapeutic effects when applied in advanced murine atherosclerosis. Its antiatherogenic impact might be associated with a suppressed adhesion to the endothelium due to down-regulation of endothelial ICAM-1 expression.

Distinct Bone Marrow Blood Vessels Differentially Regulate Normal and Malignant Hematopoietic Stem and Progenitor Cells

Bone marrow (BM) endothelial cells (BMECs) form a network of blood vessels (BVs) that regulate both leukocyte trafficking and hematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance between these dual regulatory roles and if these events occur at the same vascular site. We define the BM architecture of functionally distinct BVs, their spatial localization and association with specific stromal precursors, which cooperatively regulate HSPC fate. BM stem and progenitor cell maintenance in a metabolically non-active state and leukocyte trafficking occur at separate sites and are differentially regulated by specific BVs with distinct permeability properties. BM arteries were found to be mostly encircled by aSMA+ pericytes whereas the ensuing small-diameter endosteal and trabecular arterioles were predominantly surrounded by stem cell-niche supporting stromal precursor cells. Live imaging and flow analysis revealed that endosteal arteriole BVs exhibited high flow rate, low permeability to external plasma from the peripheral blood, and high levels of adhesion- and tight-junction molecules. Primitive HSPCs located in peri-arteriole regions were found in a non-activated, low reactive oxygen species (ROS) state. Exposure of BM HSPCs to peripheral blood plasma, enhanced their metabolic activity, exhibited by enhanced intracellular ROS levels, and glucose uptake. The same was also evident for circulating HSPCs in the blood. Plasma-exposed HSPCs displayed enhanced motility alongside with reduced long-term repopulation potential. Live imaging showed that all immature and mature leukocyte bi-directional trafficking occurred exclusively at the more permeable sinusoids, located downstream to the endosteal arterioles. Of note, BM sinusoids contained a higher prevalence of ROShigh cells in their microenvironment, including HSPCs. Rapid AMD3100-induced HSPC mobilization preferentially affected sinusoidal but not arterial BVs permeability and CXCL12 chemokine release. Endothelial specific in vivo interference with CXCL12-CXCR4 interactions, via conditional CXCR4 genetic deletion, hampered BM barrier integrity resulting in enhanced HSPC egress. In line with these results we found that during conditions favoring BM stem and progenitor cells expansion, endothelial integrity was enhanced along with reduced HSPC bi-directional trafficking. Conversely, conditional endothelial specific induced genetic or pharmacologic disruption of barrier integrity augmented ROS levels in HSPCs, enhancing their bi-directional trafficking and differentiation while reducing their BM pool size and maintenance in a metabolically non-active state. Of note, humanized mice engrafted with pre-B ALL cells exhibited reduced BM barrier permeability most probably due to BM endothelium modification via FGF-2 secretion by the leukemic clone. Interestingly, human pre-B ALL cells displayed hypersensitivity to plasmatic exposure. We hypothesize that malignant cells modify BM endothelium to provide themselves with a supportive and protective microenvironment composed of undifferentiated BM stromal progenitors and tightly sealed endothelial barrier. In conclusion, our study identifies anatomically distinct BM BVs with different barrier functions serving as systemic leukocyte trafficking or HSPC BM maintenance sites with clinical therapeutic relevance. DisclosuresRafii:Angiocrine Bioscience: Consultancy, Equity Ownership.

Acute Effects of Smoking on Heart Rate and Peripheral Resistance in Young Smokers

SummarySmoking has many harmful effects on human body. It is well known that smoking is one of the most important risk factors for cardiovascular diseases. Though the ingredients from cigarette smoke stimulate the release of vasoconstrictor and reduce the release of vasodilator substances, the goal of this study was to investigate the acute effects of smoking on arterial blood pressure, heart rate and blood vessel flow.The investigation was conducted on forty healthy volunteers divided into two groups of twenty non-smokers (control group), and twenty smokers (experimental group). The group of smokers was examined before and after smoking four cigarettes during one hour. Blood pressure and electrocardiograph (ECG) were measured by common methods. Brecht’s and Boucke’s methods of plethysmography were used to evaluate the peripheral circulation.There were no differences in measured systolic and diastolic blood pressure and recorded ECG between non-smokers and smokers, neither between smokers before and after smoking. However, heart rate was increased by 29.57% after smoking in comparison to the value before smoking.Evaluation of plethysmographic parameters showed that amplitude was significantly decreased. Parameters of peripheral resistance were very increased: ductility was decreased by over 20%.It can be concluded that acute smoking does not significantly affect the level of blood pressure, although it increases heart rate. The shape of plethysmograms showed decreased systolic filling and decreased diameters of blood vessels.