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Substrate stiffness heterogeneities disrupt endothelial barrier integrity in a micropillar model of heterogeneous vascular stiffening.
VanderBurgh JA, Hotchkiss H, Potharazu A, Taufalele PV, Reinhart-King CA
(2018) Integr Biol (Camb) 10: 734-746
MeSH Terms: Adherens Junctions, Animals, Aorta, Atherosclerosis, Cattle, Cell Adhesion, Cell Communication, Cell Movement, Dimethylpolysiloxanes, Endothelial Cells, Endothelium, Vascular, Focal Adhesions, Human Umbilical Vein Endothelial Cells, Humans, Leukocytes, Materials Testing, Neutrophils, Phenotype, Tunica Intima, Vascular Stiffness, Vinculin
Show Abstract · Added April 10, 2019
Intimal stiffening has been linked with increased vascular permeability and leukocyte transmigration, hallmarks of atherosclerosis. However, recent evidence indicates age-related intimal stiffening is not uniform but rather characterized by increased point-to-point heterogeneity in subendothelial matrix stiffness, the impact of which is much less understood. To investigate the impact of spatially heterogeneous matrix rigidity on endothelial monolayer integrity, we develop a micropillar model to introduce closely-spaced, step-changes in substrate rigidity and compare endothelial monolayer phenotype to rigidity-matched, uniformly stiff and compliant substrates. We found equivalent disruption of adherens junctions within monolayers on step-rigidity and uniformly stiff substrates relative to uniformly compliant substrates. Similarly, monolayers cultured on step-rigidity substrates exhibited equivalent percentages of leukocyte transmigration to monolayers on rigidity-matched, uniformly stiff substrates. Adherens junction tension and focal adhesion density, but not size, increased within monolayers on step-rigidity and uniformly stiff substrates compared to more compliant substrates suggesting that elevated tension is disrupting adherens junction integrity. Leukocyte transmigration frequency and time, focal adhesion size, and focal adhesion density did not differ between stiff and compliant sub-regions of step-rigidity substrates. Overall, our results suggest that endothelial monolayers exposed to mechanically heterogeneous substrates adopt the phenotype associated with the stiffer matrix, indicating that spatial heterogeneities in intimal stiffness observed with age could disrupt endothelial barrier integrity and contribute to atherogenesis.
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21 MeSH Terms
Epithelial Heparan Sulfate Contributes to Alveolar Barrier Function and Is Shed during Lung Injury.
Haeger SM, Liu X, Han X, McNeil JB, Oshima K, McMurtry SA, Yang Y, Ouyang Y, Zhang F, Nozik-Grayck E, Zemans RL, Tuder RM, Bastarache JA, Linhardt RJ, Schmidt EP
(2018) Am J Respir Cell Mol Biol 59: 363-374
MeSH Terms: Animals, Capillary Permeability, Endothelium, Vascular, Glycocalyx, Heparitin Sulfate, Lipopolysaccharides, Lung Injury, Mice, Respiratory Distress Syndrome, Adult, Syndecans
Show Abstract · Added May 31, 2018
The lung epithelial glycocalyx is a carbohydrate-enriched layer lining the pulmonary epithelial surface. Although epithelial glycocalyx visualization has been reported, its composition and function remain unknown. Using immunofluorescence and mass spectrometry, we identified heparan sulfate (HS) and chondroitin sulfate within the lung epithelial glycocalyx. In vivo selective enzymatic degradation of epithelial HS, but not chondroitin sulfate, increased lung permeability. Using mass spectrometry and gel electrophoresis approaches to determine the fate of epithelial HS during lung injury, we detected shedding of 20 saccharide-long or greater HS into BAL fluid in intratracheal LPS-treated mice. Furthermore, airspace HS in clinical samples from patients with acute respiratory distress syndrome correlated with indices of alveolar permeability, reflecting the clinical relevance of these findings. The length of HS shed during intratracheal LPS-induced injury (≥20 saccharides) suggests cleavage of the proteoglycan anchoring HS to the epithelial surface, rather than cleavage of HS itself. We used pharmacologic and transgenic animal approaches to determine that matrix metalloproteinases partially mediate HS shedding during intratracheal LPS-induced lung injury. Although there was a trend toward decreased alveolar permeability after treatment with the matrix metalloproteinase inhibitor, doxycycline, this did not reach statistical significance. These studies suggest that epithelial HS contributes to the lung epithelial barrier and its degradation is sufficient to increase lung permeability. The partial reduction of HS shedding achieved with doxycycline is not sufficient to rescue epithelial barrier function during intratracheal LPS-induced lung injury; however, whether complete attenuation of HS shedding is sufficient to rescue epithelial barrier function remains unknown.
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10 MeSH Terms
A Metabolic Basis for Endothelial-to-Mesenchymal Transition.
Xiong J, Kawagishi H, Yan Y, Liu J, Wells QS, Edmunds LR, Fergusson MM, Yu ZX, Rovira II, Brittain EL, Wolfgang MJ, Jurczak MJ, Fessel JP, Finkel T
(2018) Mol Cell 69: 689-698.e7
MeSH Terms: 3-Hydroxyacyl CoA Dehydrogenases, Acetyl Coenzyme A, Acetyl-CoA C-Acyltransferase, Animals, Carbon-Carbon Double Bond Isomerases, Carnitine O-Palmitoyltransferase, Cells, Cultured, Endothelium, Vascular, Enoyl-CoA Hydratase, Epithelial-Mesenchymal Transition, Fatty Acids, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidation-Reduction, Racemases and Epimerases, Signal Transduction, Transforming Growth Factor beta
Show Abstract · Added March 14, 2018
Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor β (TGF-β) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2 mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
Copyright © 2018 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function.
Komalavilas P, Luo W, Guth CM, Jolayemi O, Bartelson RI, Cheung-Flynn J, Brophy CM
(2017) PLoS One 12: e0188069
MeSH Terms: Animals, Endothelium, Vascular, Female, Nitric Oxide, Phosphorylation, Rats, Rats, Sprague-Dawley, Receptors, Purinergic P2X7, Vascular Surgical Procedures, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added May 22, 2018
A viable vascular endothelial layer prevents vasomotor dysfunction, thrombosis, inflammation, and intimal hyperplasia. Injury to the endothelium occurs during harvest and "back table" preparation of human saphenous vein prior to implantation as an arterial bypass conduit. A subfailure overstretch model of rat aorta was used to show that subfailure stretch injury of vascular tissue leads to impaired endothelial-dependent relaxation. Stretch-induced impaired relaxation was mitigated by treatment with purinergic P2X7 receptor (P2X7R) inhibitors, brilliant blue FCF (FCF) and A740003, or apyrase, an enzyme that catalyzes the hydrolysis of ATP. Alternatively, treatment of rat aorta with exogenous ATP or 2'(3')-O-(4-Benzoyl benzoyl)-ATP (BzATP) also impaired endothelial-dependent relaxation. Treatment of human saphenous vein endothelial cells (HSVEC) with exogenous ATP led to reduced nitric oxide production which was associated with increased phosphorylation of the stress activated protein kinase, p38 MAPK. ATP- stimulated p38 MAPK phosphorylation of HSVEC was inhibited by FCF and SB203580. Moreover, ATP inhibition of nitric oxide production in HSVEC was prevented by FCF, SB203580, L-arginine supplementation and arginase inhibition. Finally, L-arginine supplementation and arginase inhibition restored endothelial dependent relaxation after stretch injury of rat aorta. These results suggest that vascular stretch injury leads to ATP release, activation of P2X7R and p38 MAPK resulting in endothelial dysfunction due to arginase activation. Endothelial function can be restored in both ATP treated HSVEC and intact stretch injured rat aorta by P2X7 receptor inhibition with FCF or L-arginine supplementation, implicating straightforward therapeutic options for treatment of surgical vascular injury.
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MeSH Terms
Ascorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin.
Kuck JL, Bastarache JA, Shaver CM, Fessel JP, Dikalov SI, May JM, Ware LB
(2018) Biochem Biophys Res Commun 495: 433-437
MeSH Terms: Antioxidants, Ascorbic Acid, Capillary Permeability, Endothelium, Vascular, Hemoglobins, Human Umbilical Vein Endothelial Cells, Humans, Sepsis
Show Abstract · Added March 14, 2018
BACKGROUND - Increased endothelial permeability is central to shock and organ dysfunction in sepsis but therapeutics targeted to known mediators of increased endothelial permeability have been unsuccessful in patient studies. We previously reported that cell-free hemoglobin (CFH) is elevated in the majority of patients with sepsis and is associated with organ dysfunction, poor clinical outcomes and elevated markers of oxidant injury. Others have shown that Vitamin C (ascorbate) may have endothelial protective effects in sepsis. In this study, we tested the hypothesis that high levels of CFH, as seen in the circulation of patients with sepsis, disrupt endothelial barrier integrity.
METHODS - Human umbilical vein endothelial cells (HUVEC) were grown to confluence and treated with CFH with or without ascorbate. Monolayer permeability was measured by Electric Cell-substrate Impedance Sensing (ECIS) or transfer of C-inulin. Viability was measured by trypan blue exclusion. Intracellular ascorbate was measured by HPLC.
RESULTS - CFH increased permeability in a dose- and time-dependent manner with 1 mg/ml of CFH increasing inulin transfer by 50% without affecting cell viability. CFH (1 mg/ml) also caused a dramatic reduction in intracellular ascorbate in the same time frame (1.4 mM without CFH, 0.23 mM 18 h after 1 mg/ml CFH, p < 0.05). Pre-treatment of HUVECs with ascorbate attenuated CFH induced permeability.
CONCLUSIONS - CFH increases endothelial permeability in part through depletion of intracellular ascorbate. Supplementation of ascorbate can attenuate increases in permeability mediated by CFH suggesting a possible therapeutic approach in sepsis.
Copyright © 2017 Elsevier Inc. All rights reserved.
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8 MeSH Terms
Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension.
Suzuki T, Carrier EJ, Talati MH, Rathinasabapathy A, Chen X, Nishimura R, Tada Y, Tatsumi K, West J
(2018) Am J Physiol Lung Cell Mol Physiol 314: L118-L126
MeSH Terms: Animals, Antigens, CD, Cadherins, Cells, Cultured, Endothelium, Vascular, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Humans, Hypertension, Pulmonary, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pulmonary Artery
Show Abstract · Added March 26, 2019
Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sor/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation.
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MeSH Terms
Real-time imaging of VCAM-1 mRNA in TNF-α activated retinal microvascular endothelial cells using antisense hairpin-DNA functionalized gold nanoparticles.
Uddin MI, Jayagopal A, Wong A, McCollum GW, Wright DW, Penn JS
(2018) Nanomedicine 14: 63-71
MeSH Terms: Animals, Cell Survival, Cells, Cultured, DNA, Antisense, Endothelium, Vascular, Fluorescence, Gold, Metal Nanoparticles, Mice, Molecular Imaging, RNA, Messenger, Retinal Vessels, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1
Show Abstract · Added December 21, 2017
Vascular cell adhesion molecule 1 (VCAM-1) is an important inflammatory biomarker correlating with retinal disease progression. Thus, detection of VCAM-1 mRNA expression levels at an early disease stage could be an important predictive biomarker to assess the risk of disease progression and monitoring treatment response. We have developed VCAM-1 targeted antisense hairpin DNA-functionalized gold nanoparticles (AS-VCAM-1 hAuNP) for the real time detection of VCAM-1 mRNA expression levels in retinal endothelial cells. The AS-VCAM-1 hAuNP fluorescence enhancement clearly visualized the TNF-α induced cellular VCAM-1 mRNA levels with high signal to noise ratios compared to normal serum treated cells. The scrambled hAuNP probes were minimally detectable under same image acquisition conditions. Intracellular hAuNPs were detected using transmission electron microscopy (TEM) analysis of the intact cells. In addition, the AS-VCAM-1 hAuNP probes exhibited no acute toxicity to the retinal microvascular endothelial cells as measured by live-dead assay.
Copyright © 2017 Elsevier Inc. All rights reserved.
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2 Members
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14 MeSH Terms
Unregulated saphenous vein graft distension decreases tissue viscoelasticity.
Wise ES, Hocking KM, Evans BC, Duvall CL, Cheung-Flynn J, Brophy CM
(2017) Perfusion 32: 489-494
MeSH Terms: Animals, Coronary Artery Bypass, Endothelium, Vascular, Humans, Saphenous Vein, Swine, Vasoconstriction
Show Abstract · Added March 14, 2018
OBJECTIVES - Unregulated intraoperative distension of human saphenous vein (SV) graft leads to supraphysiologic luminal pressures and causes acute physiologic and cellular injury to the conduit. The effect of distension on tissue viscoelasticity, a biophysical property critical to a successful graft, is not well described. In this investigation, we quantify the loss of viscoelasticity in SV deformed by distension and compare the results to tissue distended in a pressure-controlled fashion.
MATERIALS AND METHODS - Unmanipulated porcine SV was used as a control or distended without regulation and distended with an in-line pressure release valve (PRV). Rings were cut from these tissues and suspended on a muscle bath. Force versus time tracings of tissue constricted with KCl (110 mM) and relaxed with sodium nitroprusside (SNP) were fit to the Hill model of viscoelasticity, using mean absolute error (MAE) and r-goodness of fit as measures of conformity.
RESULTS - One-way ANOVA analysis demonstrated that, in tissue distended manually, the MAE was significantly greater and the r-goodness of fit was significantly lower than both undistended tissues and tissues distended with a PRV (p<0.05) in KCl-induced vasoconstriction and SNP-induced vasodilation.
CONCLUSIONS - Unregulated manual distension of SV graft causes loss of viscoelasticity and such loss may be mitigated with the use of an in-line PRV.
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7 MeSH Terms
Expression of receptor-type protein tyrosine phosphatase in developing and adult renal vasculature.
Takahashi K, Kim R, Lauhan C, Park Y, Nguyen NG, Vestweber D, Dominguez MG, Valenzuela DM, Murphy AJ, Yancopoulos GD, Gale NW, Takahashi T
(2017) PLoS One 12: e0177192
MeSH Terms: Animals, Endothelium, Vascular, Kidney, Mice, Phosphorylation, Promoter Regions, Genetic, Protein Tyrosine Phosphatases, Receptor Protein-Tyrosine Kinases
Show Abstract · Added April 6, 2018
Renal vascular development is a coordinated process that requires ordered endothelial cell proliferation, migration, intercellular adhesion, and morphogenesis. In recent decades, studies have defined the pivotal role of endothelial receptor tyrosine kinases (RPTKs) in the development and maintenance of renal vasculature. However, the expression and the role of receptor tyrosine phosphatases (RPTPs) in renal endothelium are poorly understood, though coupled and counterbalancing roles of RPTKs and RPTPs are well defined in other systems. In this study, we evaluated the promoter activity and immunolocalization of two endothelial RPTPs, VE-PTP and PTPμ, in developing and adult renal vasculature using the heterozygous LacZ knock-in mice and specific antibodies. In adult kidneys, both VE-PTP and PTPμ were expressed in the endothelium of arterial, glomerular, and medullary vessels, while their expression was highly limited in peritubular capillaries and venous endothelium. VE-PTP and PTPμ promoter activity was also observed in medullary tubular segments in adult kidneys. In embryonic (E12.5, E13.5, E15.5, E17.5) and postnatal (P0, P3, P7) kidneys, these RPTPs were expressed in ingrowing renal arteries, developing glomerular microvasculature (as early as the S-shaped stage), and medullary vessels. Their expression became more evident as the vasculatures matured. Peritubular capillary expression of VE-PTP was also noted in embryonic and postnatal kidneys. Compared to VE-PTP, PTPμ immunoreactivity was relatively limited in embryonic and neonatal renal vasculature and evident immunoreactivity was observed from the P3 stage. These findings indicate 1) VE-PTP and PTPμ are expressed in endothelium of arterial, glomerular, and medullary renal vasculature, 2) their expression increases as renal vascular development proceeds, suggesting that these RPTPs play a role in maturation and maintenance of these vasculatures, and 3) peritubular capillary VE-PTP expression is down-regulated in adult kidneys, suggesting a role of VE-PTP in the development of peritubular capillaries.
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MeSH Terms
Autonomic Blockade Reverses Endothelial Dysfunction in Obesity-Associated Hypertension.
Gamboa A, Figueroa R, Paranjape SY, Farley G, Diedrich A, Biaggioni I
(2016) Hypertension 68: 1004-10
MeSH Terms: Autonomic Nerve Block, Blood Pressure Determination, Body Mass Index, Comorbidity, Cross-Over Studies, Disease Progression, Endothelium, Vascular, Female, Follow-Up Studies, Humans, Hypertension, Male, Middle Aged, Nitric Oxide, Nitroprusside, Obesity, Risk Assessment, Severity of Illness Index
Show Abstract · Added October 14, 2016
Impaired nitric oxide (NO) vasodilation (endothelial dysfunction) is associated with obesity and thought to be a factor in the development of hypertension. We previously found that NO synthesis inhibition had similar pressor effects in obese hypertensives compared with healthy control during autonomic blockade, suggesting that impaired NO vasodilation is secondary to sympathetic activation. We tested this hypothesis by determining the effect of autonomic blockade (trimethaphan 4 mg/min IV) on NO-mediated vasodilation (increase in forearm blood flow to intrabrachial acetylcholine) compared with endothelial-independent vasodilation (intrabrachial sodium nitroprusside) in obese hypertensive subjects (30© 2016 American Heart Association, Inc.
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18 MeSH Terms