ROCK and cAMP Promote Lymphatic Endothelial Cell Barrier Integrity and Modulate Histamine and Thrombin-Induced Barrier Dysfunction

Breslin, Jerome W.

doi:10.1089/lrb.2010.0016

Cited by 38 publications

(48 citation statements)

References 47 publications

(80 reference statements)

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“…Because of this we decided to utilize in vitro measures of barrier function in cultured RLECs to eliminate the confounding factors of the immune cells. While this may not completely recapitulate events in vivo, it does provide direct evidence how the lymphatic endothelium may responds to inflammation [23,35,26]. …”

Section: Discussionmentioning

confidence: 99%

The effects of inflammatory cytokines on lymphatic endothelial barrier function

Cromer

Zawieja

Tharakan³

et al. 2013

Angiogenesis

111

107

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Proper lymphatic function is necessary for the transport of fluids, macromolecules, antigens and immune cells out of the interstitium. The lymphatic endothelium plays important roles in the modulation of lymphatic contractile activity and lymph transport, but it's role as a barrier between the lymph and interstitial compartments is less well understood. Alterations in lymphatic function have long been associated with edema and inflammation although the integrity of the lymphatic endothelial barrier during inflammation is not well-defined. In this paper we evaluated the integrity of the lymphatic barrier in response to inflammatory stimuli commonly associated with increased blood endothelial permeability. We utilized in vitro assays of lymphatic endothelial cell (LEC) monolayer barrier function after treatment with different inflammatory cytokines and signaling molecules including TNF-α, IL-6, IL-1β, IFN-γ and LPS. Moderate increases in an index of monolayer barrier dysfunction were noted with all treatments (20–60% increase) except IFN-γ which caused a greater than 2.5 fold increase. Cytokine-induced barrier dysfunction was blocked or reduced by the addition of LNAME, except for IL-1β and LPS treatments, suggesting a regulatory role for nitric oxide. The decreased LEC barrier was associated with modulation of both intercellular adhesion and intracellular cytoskeletal activation. Cytokine treatments reduced the expression of VE-cadherin and increased scavenging of β-catenin in the LECs and this was partially reversed by LNAME. Likewise the phosphorylation of myosin light chain 20 at the regulatory serine 19 site, which accompanied the elevated monolayer barrier dysfunction in response to cytokine treatment, was also blunted by LNAME application. This suggests that the lymphatic barrier is regulated during inflammation and that certain inflammatory signals may induce large increases in permeability.

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Section: Discussionmentioning

confidence: 99%

The effects of inflammatory cytokines on lymphatic endothelial barrier function

Cromer

Zawieja

Tharakan³

et al. 2013

Angiogenesis

111

107

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“…Indeed, complex and even opposite effects of histamine on the lymphatic function have been reported. Thus, histamine appeared to stimulate the lymphatic vessel contractile activity ( 36 ), to act as an endothelium-derived relaxing factor in mesenteric lymphatic vessels ( 37 ), or to disrupt the integrity of the barrier function of lymphatic endothelial cells, thereby potentiating leakage of solutes from lymph back to the interstitial space ( 38 ). Whether the second dose of histamine had also activated the lymphatic SR-BI transporter recently found to regulate the entry of HDL into the lymphatic vessels ( 14 ) remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Enhanced vascular permeability facilitates entry of plasma HDL and promotes macrophage-reverse cholesterol transport from skin in mice

Kareinen

Cedó

Silvennoinen

et al. 2015

Journal of Lipid Research

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Supplementary key words bradykinin • cholesterol • foam cells • high density lipoprotein • histamine • lipoproteins • mast cells • serotoninVascular endothelium is a semipermeable barrier that regulates the solute composition of interstitial fl uids by an ultrafi ltration process of various blood components ( 1 ). Such a sieving effect also determines the passage through the endothelium of the various types of lipoproteins, which are the largest blood solutes. It was an early observation in hypercholesterolemic rabbits that the arterial infl ux of plasma HDL, LDL, and VLDL decreases linearly with the logarithm of the diameter of the lipoprotein particles ( 2 ). Studies in humans and other mammalian species also indicated that the fl ux of LDL from plasma into the arterial wall depends not only on its plasma concentration but also on its permeability at the plasma-arterial wall interface ( 3 ).Accumulation of excess cholesterol in cytoplasmic lipid droplets of macrophages in the arterial intima is a primary event in atherosclerosis. Accordingly, an efficient control of the cholesterol pool in the arterial foam cells is essential to prevent progression of the disease or even to induce its regression. In general, control of cellular cholesterol balance is partially achieved by the transfer of cellular cholesterol from peripheral body compartments to the liver and ultimately to the gut for its fecal excretion along a pathway that is known as the reverse cholesterol transport (RCT) ( 4 ). Effl ux of cellular

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“…Transendothelial electrical resistance (TER) was determined as an index of endothelial barrier function as previously described6, 20 with an electrical cell‐substrate impedance sensing 1600R system (Applied Biophysics, Troy, NY). Briefly, cells were cultured (10 5 cells/cm 2 ) on 8W1E small gold electrode arrays (Applied Biophysics).…”

Section: Methodsmentioning

confidence: 99%

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

Breslin

Daines

Doggett

et al. 2016

JAHA

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BackgroundMicrovascular leakage of plasma proteins is a hallmark of inflammation that leads to tissue dysfunction. There are no current therapeutic strategies to reduce microvascular permeability. The purpose of this study was to identify the role of Rnd3, an atypical Rho family GTPase, in the control of endothelial barrier integrity. The potential therapeutic benefit of Rnd3 protein delivery to ameliorate microvascular leakage was also investigated.Methods and ResultsUsing immunofluorescence microscopy, Rnd3 was observed primarily in cytoplasmic areas around the nuclei of human umbilical vein endothelial cells. Permeability to fluorescein isothiocyanate–albumin and transendothelial electrical resistance of human umbilical vein endothelial cell monolayers served as indices of barrier function, and RhoA, Rac1, and Cdc42 activities were determined using G‐LISA assays. Overexpression of Rnd3 significantly reduced the magnitude of thrombin‐induced barrier dysfunction, and abolished thrombin‐induced Rac1 inactivation. Depleting Rnd3 expression with siRNA significantly extended the time course of thrombin‐induced barrier dysfunction and Rac1 inactivation. Time‐lapse microscopy of human umbilical vein endothelial cells expressing GFP‐actin showed that co‐expression of mCherry‐Rnd3 attenuated thrombin‐induced reductions in local lamellipodia that accompany endothelial barrier dysfunction. Lastly, a novel Rnd3 protein delivery method reduced microvascular leakage in a rat model of hemorrhagic shock and resuscitation, assessed by both intravital microscopic observation of extravasation of fluorescein isothiocyanate–albumin from the mesenteric microcirculation, and direct determination of solute permeability in intact isolated venules.ConclusionsThe data suggest that Rnd3 can shift the balance of RhoA and Rac1 signaling in endothelial cells. In addition, our findings suggest the therapeutic, anti‐inflammatory potential of delivering Rnd3 to promote endothelial barrier recovery during inflammatory challenge.

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ROCK and cAMP Promote Lymphatic Endothelial Cell Barrier Integrity and Modulate Histamine and Thrombin-Induced Barrier Dysfunction

Cited by 38 publications

References 47 publications

The effects of inflammatory cytokines on lymphatic endothelial barrier function

The effects of inflammatory cytokines on lymphatic endothelial barrier function

Enhanced vascular permeability facilitates entry of plasma HDL and promotes macrophage-reverse cholesterol transport from skin in mice

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

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