Early stages of endothelial wound repair: conversion of quiescent to migrating endothelial cells involves tyrosine phosphorylation and actin microfilament reorganization

Lee, Tsu-Yee Joseph; Gotlieb, Avrum I.

doi:10.1007/s004410051370

Cited by 24 publications

(20 citation statements)

References 42 publications

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“…46,47 Myofibroblast ␣-SMA expression and its assembly into stress fibers are important in cell migration, force generation, and wound contracture both in vitro and in vivo. 48,49 In our model it is likely the increased stress fibers at the WE is associated with elongation and migration of the VICs into the wound.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates in Vitro Heart Valve Repair by Activated Valve Interstitial Cells

Liu

Gotlieb

2008

The American Journal of Pathology

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100

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The regulation of valve interstitial cell (VIC) function in response to tissue injury and valve disease is not well understood. Because transforming growth factor-␤ (TGF-␤) has been implicated in tissue repair, we tested the hypothesis that TGF-␤ is a regulator of VIC activation and associated cell responses that occur during early repair processes. We used a well-characterized wound model that was created by mechanical denudation of a confluent VIC monolayer to study activation and repair 24 hours after wounding. VIC activation was demonstrated by immunofluorescent localization of ␣-smooth muscle actin (␣-SMA), and ␣-SMA mRNA levels were quantified by real-time polymerase chain reaction. Proliferation and apoptosis were quantified by bromodeoxyuridine staining and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Repair was quantified by measuring VIC extension into the wound , and TGF-␤ expression was shown by immunofluorescent localization of intracellular TGF-␤. Compared with nonwounded monolayers, VICs at the wound edge showed ␣-SMA staining, increased ␣-SMA mRNA content, elongation into the wound with stress fibers, proliferation, and apoptosis. VICs at the wound edge also showed increased TGF-␤ and pSmad2/3 staining with co-expression of ␣-SMA. Addition of TGF-␤ neutralizing antibody to the wound decreased VIC activation, ␣-SMA mRNA content, proliferation, apoptosis, wound closure rate, and stress fibers. Conversely, exogenous addition of TGF-␤ to the wound increased VIC activation , proliferation , wound closure rate , and stress fibers. Thus , wounding activates VICs , and TGF-␤ signaling modulates VIC response to injury.

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates in Vitro Heart Valve Repair by Activated Valve Interstitial Cells

Liu

Gotlieb

2008

The American Journal of Pathology

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100

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“…Recent studies (9,57,63,64) have shown a correlation between increased phosphorylation of TJ proteins (ZO-1, ZO-2, and occludin) and increased permeability in both kidney and brain cell culture models. Indeed, it has been suggested that changes in phosphorylation of these cellular proteins is responsible for perturbations in cell-to-cell adhesion (40,63). Whereas a 2.3-fold increase in tyrosine phosphorylation was seen in aortic endothelial cells exposed to 4-h hypoxia with 30-s posthypoxic reoxygenation (12), it is not clear which proteins are phosphorylated.…”

Section: Discussionmentioning

confidence: 99%

Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation

Mark

Davis

2002

American Journal of Physiology-Heart and Circulatory Physiology

342

272

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Mark, Karen S., and Thomas P. Davis. Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol Heart Circ Physiol 282: H1485-H1494, 2002; 10.1152/ajpheart.00645.2001.-Cerebral microvessel endothelial cells that form the bloodbrain barrier (BBB) have tight junctions (TJ) that are critical for maintaining brain homeostasis and low permeability. Both integral (claudin-1 and occludin) and membrane-associated zonula occluden-1 and -2 (ZO-1 and ZO-2) proteins combine to form these TJ complexes that are anchored to the cytoskeletal architecture (actin). Disruptions of the BBB have been attributed to hypoxic conditions that occur with ischemic stroke, pathologies of decreased perfusion, and high-altitude exposure. The effects of hypoxia and posthypoxic reoxygenation in cerebral microvasculature and corresponding cellular mechanisms involved in disrupting the BBB remain unclear. This study examined hypoxia and posthypoxic reoxygenation effects on paracellular permeability and changes in actin and TJ proteins using primary bovine brain microvessel endothelial cells (BBMEC). Hypoxia induced a 2.6-fold increase in [ 14 C]sucrose, a marker of paracellular permeability. This effect was significantly reduced (ϳ58%) with posthypoxic reoxygenation. After hypoxia and posthypoxic reoxygenation, actin expression was increased (1.4-and 2.3-fold, respectively). Whereas little change was observed in TJ protein expression immediately after hypoxia, a twofold increase in expression was seen with posthypoxic reoxygenation. Furthermore, immunofluorescence studies showed alterations in occludin, ZO-1, and ZO-2 protein localization during hypoxia and posthypoxic reoxygenation that correlate with the observed changes in BBMEC permeability. The results of this study show hypoxia-induced changes in paracellular permeability may be due to perturbation of TJ complexes and that posthypoxic reoxygenation reverses these effects. endothelial cells; cytoarchitecture; blood-brain barrier; immunofluorescence WHEREAS RESEARCH INVOLVING hypoxic stress has traditionally focused on identifying and treating risk factors associated with ischemic stroke (17,18,43), hypoxia as a result of high-altitude exposure has also been associated with impairment in neurological function (26,37). Early intervention after ischemic stroke has been shown to reduce tissue damage associated with increased cerebrovascular permeability (7, 39). Recently, research has expanded into examining cellular effects of cerebral ischemia-reperfusion. Ischemic stroke is a reduction or cessation of blood flow to the brain, which deprives the cerebral tissue of important nutrients and oxygen as well as removal of metabolic waste products. Whereas this decrease in oxygen supply to the brain (i.e., hypoxia) has been shown to increase cerebrovascular permeability (1,19), there are also reports (42, 66) of increased permeability in peripheral and cerebral endothelial cells during posthypoxic reperfusion (i.e., reoxygenation). Little is know...

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“…trans-Resveratrol significantly inhibits the ability of GM7373 cells ( Fig. 2A) and MAECs (data not shown) to repair a wounded monolayer, a phenomenon that depends on the migratory and proliferative activity of the cells at the edge of the wound (32). Also, as shown in Fig.…”

Section: In Vitro Effects Of Resveratrol Stereoisomers On Different Smentioning

confidence: 97%

αvβ3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers

Belleri

Ribatti

Savio

et al. 2008

Molecular Cancer Therapeutics

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Angiogenesis is target for antineoplastic and chemopreventive therapies. The natural phytoalexin resveratrol is found in grapes and red wine as cis and trans stereoisomers. trans-Resveratrol shows antiangiogenic activity, but its mechanism of action is not fully elucidated. Recently, trans-resveratrol has been shown to interact with the B 3 integrin subunit, raising the possibility that inhibition of endothelial A v B 3 integrin function may concur to its angiosuppressive activity. To get novel insights about the antiangiogenic activity of resveratrol, we compared cis-and trans-resveratrol stereoisomers for their effect on the angiogenesis process and endothelial A v B 3 integrin function. trans-Resveratrol inhibits endothelial cell proliferation and the repair of mechanically wounded endothelial cell monolayers. Also, it prevents endothelial cell sprouting in fibrin gel, collagen gel invasion, and morphogenesis on Matrigel. In vivo, trans-resveratrol inhibits vascularization of the chick embryo area vasculosa and murine melanoma B16 tumor growth and neovascularization. In all the assays, cis-resveratrol exerts a limited, if any, effect. In keeping with these observations, transresveratrol, but not cis-resveratrol, inhibits A v B 3 integrindependent endothelial cell adhesion and the recruitment of enhanced green fluorescent protein-tagged B 3 integrin in focal adhesion contacts. In conclusion, stereoisomery affects the antiangiogenic activity of resveratrol, the trans isomer being significantly more potent than the cis isoform. The different antiangiogenic potential of resveratrol stereoisomers is related, at least in part, to their different capacity to affect A v B 3 integrin function. This may have profound implications for the design of synthetic antiangiogenic/angiopreventive phytoalexin derivatives.

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Early stages of endothelial wound repair: conversion of quiescent to migrating endothelial cells involves tyrosine phosphorylation and actin microfilament reorganization

Cited by 24 publications

References 42 publications

Transforming Growth Factor-β Regulates in Vitro Heart Valve Repair by Activated Valve Interstitial Cells

Transforming Growth Factor-β Regulates in Vitro Heart Valve Repair by Activated Valve Interstitial Cells

Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation

αvβ3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers

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