Effect of Vascular Endothelial Growth Factor on Cultured Endothelial Cell Monolayer Transport Properties

Chang, Yong S.; Munn, Lance L.; Hillsley, Mechteld V.; Dull, Randal O.; Yuan, Junhua; Lakshminarayanan, Sunitha; Gardner, Thomas W.; Jain, Rakesh K.; Tarbell, John M.

doi:10.1006/mvre.1999.2225

Cited by 113 publications

(75 citation statements)

References 32 publications

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“…Thrombin induced vascular permeability dynamics of a similar nature in BAOECs have been elucidated in previous studies. [34][35][36]44,45 Figure 2 the tracer molecule in the abluminal channel is divided by the corresponding luminal concentration and compared along with thrombin treatment time. This normalizes the effect of doing the tests at different luminal concentrations to an extent and provides insight on how the size of the tracer molecule affects permeability.…”

Section: Resultsmentioning

confidence: 99%

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

et al. 2017

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The inflammatory response in endothelial cells (ECs) leads to an increase in vascular permeability through the formation of gaps. However, the dynamic nature of vascular permeability and external factors involved is still elusive. In this work, we use a biomimetic blood vessel (BBV) microfluidic model to measure in real-time the change in permeability of the EC layer under culture in physiologically relevant flow conditions. This platform studies the dynamics and characterizes vascular permeability when the EC layer is triggered with an inflammatory agent using tracer molecules of three different sizes, and the results are compared to a transwell insert study. We also apply an analytical model to compare the permeability data from the different tracer molecules to understand the physiological and bio-transport significance of endothelial permeability based on the molecule of interest. A computational model of the BBV model is also built to understand the factors influencing transport of molecules of different sizes under flow. The endothelial monolayer cultured under flow in the BBV model was treated with thrombin, a serine protease that induces a rapid and reversible increase in endothelium permeability. On analysis of permeability data, it is found that the transport characteristics for fluorescein isothiocyanate (FITC) dye and FITC Dextran 4k Da molecules are similar in both BBV and transwell models, but FITC Dextran 70k Da molecules show increased permeability in the BBV model as convection flow (Peclet number > 1) influences the molecule transport in the BBV model. We also calculated from permeability data the relative increase in intercellular gap area during thrombin treatment for ECs in the BBV and transwell insert models to be between 12% and 15%. This relative increase was found to be within range of what we quantified from F-actin stained EC layer images. The work highlights the importance of incorporating flow in in vitro vascular models, especially in studies involving transport of large size objects such as antibodies, proteins, nano/micro particles, and cells. Published by AIP Publishing.

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Section: Resultsmentioning

confidence: 99%

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

et al. 2017

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“…During inflammation and angiogenesis, multiple factors, including tumor necrosis factor-␣ (Nwariaku et al, 2002), histamine (Leach et al, 1995;van Nieuw Amerongen et al, 1998;Andriopoulou et al, 1999), thrombin (van Nieuw Amerongen et al, 1998;Moldobaeva and Wagner, 2002), and vascular endothelial growth factor (VEGF) (Esser et al, 1998;Kevil et al, 1998;Eliceiri et al, 1999;Chang et al, 2000), increase vascular permeability by altering cell-cell adhesion, gap formation between endothelial cells, or both. Another major inducer of permeability is interleukin-8 (IL-8/ CXCL8) (Biffl et al, 1995;Fukumoto et al, 1998;Laffon et al, 1999), a chemokine of the CXC family that was initially characterized as a neutrophil chemoattractant but has recently gained prominence as a mediator of permeability and angiogenesis (Yoshimura et al, 1987;Matsushima et al, 1988;Koch et al, 1992;Strieter et al, 1995;Martins-Green and Feugate, 1998;Addison et al, 2000;Li et al, 2002Li et al, , 2003Heidemann et al, 2003;Yao et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

Petreaca

Yao²,

Liu³

et al. 2007

MBoC

185

145

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Interleukin-8 (IL-8/CXCL8) is a chemokine that increases endothelial permeability during early stages of angiogenesis. However, the mechanisms involved in IL-8/CXCL8-induced permeability are poorly understood. Here, we show that permeability induced by this chemokine requires the activation of vascular endothelial growth factor receptor-2 (VEGFR2/fetal liver kinase 1/KDR). IL-8/CXCL8 stimulates VEGFR2 phosphorylation in a VEGF-independent manner, suggesting VEGFR2 transactivation. We investigated the possible contribution of physical interactions between VEGFR2 and the IL-8/CXCL8 receptors leading to VEGFR2 transactivation. Both IL-8 receptors interact with VEGFR2 after IL-8/CXCL8 treatment, and the time course of complex formation is comparable with that of VEGFR2 phosphorylation. Src kinases are involved upstream of receptor complex formation and VEGFR2 transactivation during IL-8/CXCL8-induced permeability. An inhibitor of Src kinases blocked IL-8/CXCL8-induced VEGFR2 phosphorylation, receptor complex formation, and endothelial permeability. Furthermore, inhibition of the VEGFR abolishes RhoA activation by IL-8/CXCL8, and gap formation, suggesting a mechanism whereby VEGFR2 transactivation mediates IL-8/CXCL8-induced permeability. This study points to VEGFR2 transactivation as an important signaling pathway used by chemokines such as IL-8/CXCL8, and it may lead to the development of new therapies that can be used in conditions involving increases in endothelial permeability or angiogenesis, particularly in pathological situations associated with both IL-8/CXCL8 and VEGF. INTRODUCTIONAngiogenesis is a multistep process in which quiescent blood vessels give rise to new blood vessels. After endothelial cells are exposed to an angiogenic factor, the endothelium is destabilized, leading to a decrease in endothelial cell adhesion and an increase in vascular permeability. Simultaneously, matrix metalloproteinases are produced and activated, which degrade the basal lamina in discrete regions of the blood vessel. The endothelial cells are then able to proliferate and migrate into surrounding connective tissue, forming a "sprout," or cord of endothelial cells, which subsequently develops a lumen; sprouts from adjacent arterioles and venules fuse to form a network of blood vessels.The nascent vessels then recruit periendothelial cells, smooth muscle-like cells that stabilize the endothelium by promoting basal lamina deposition and intercellular adhesions (Daniel and Abrahamson, 2000;Conway et al., 2001).During inflammation and angiogenesis, multiple factors, including tumor necrosis factor-␣ (Nwariaku et al., 2002), histamine (Leach et al., 1995;van Nieuw Amerongen et al., 1998;Andriopoulou et al., 1999), thrombin (van Nieuw Amerongen et al., 1998;Moldobaeva and Wagner, 2002), and vascular endothelial growth factor (VEGF) (Esser et al., 1998;Kevil et al., 1998;Eliceiri et al., 1999;Chang et al., 2000), increase vascular permeability by altering cell-cell adhesion, gap formation between endothelial cells, or both. Anothe...

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“…We measured control P DA to be 2.78 ϫ 10 Ϫ7 cm/s. Our laboratory has previously published P DA data for bovine aortic endothelial cell monolayers in the range of 4.5 ϫ 10 Ϫ6 cm/s (12) to 5.09 ϫ 10 Ϫ6 cm/s (20) and for human umbilical vein endothelial cell as 1.93 ϫ 10 Ϫ6 cm/s (8). All of these studies were done with the use of the same Transwell culture system, identical filter pretreatment, and similar culture duration.…”

Section: Discussionmentioning

confidence: 99%

“…For example, inflammatory agonists frequently act through multiple mechanisms, including neutrophil and mast cell activation (3,4,11); therefore, the direct effects of the test agonist on the endothelium are confounded by the release of secondary mediators. We have exploited the ability to control all aspects of the microenvironment by utilizing endothelial monolayers grown on porous substrates to measure both water (8,12,13) and solute transport (12,20) during precisely defined conditions and controlled Starling forces. Using these techniques, we have demonstrated that cultured monolayers have hydraulic conductivity coefficients and albumin permeability coefficients (P DA ) within the physiological range.…”

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confidence: 99%

Quantitative assessment of hemoglobin-induced endothelial barrier dysfunction

Dull

DeWitt

Dinavahi

et al. 2004

Journal of Applied Physiology

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ticelli. Quantitative assessment of hemoglobin-induced endothelial barrier dysfunction. J Appl Physiol 97: 1930 -1937, 2004. First published July 23, 2004 doi:10.1152/japplphysiol.00102.2004.-Hemoglobin (Hb)-based O 2 carriers (HBOC) are undergoing extensive development as potential "blood substitutes." A major problem associated with these molecules is an increase in microvascular permeability and peripheral vascular resistance. In this paper, we utilized bovine lung microvascular endothelial cell monolayers and simultaneously measured Hb-induced changes in transendothelial electrical resistance, diffusive albumin permeability, and diffusive Hb permeability (P DH) for three forms of Hb: natural tetrameric human Hb-A and two polymerized recombinant HBOCs containing ␣-human and ␤-bovine chains designated Hb-Polytaur (molecular mass: 500 kDa) and Hb-(Polytaur) n (molecular mass: ϳ1,000,000 Da), respectively. Hb-Polytaur and Hb-(Polytaur)n are being evaluated for clinical use as HBOCs. All three Hb molecules induce a rapid decline of transendothelial electrical resistance to 30% of baseline. Diffusive albumin permeabiltiy increases, on average, approximately ninefold (2.78 ϫ 10 Ϫ7 vs. 2.47 ϫ 10 Ϫ6 cm/s) in response to Hb exposure. All three Hb molecules induce an increase in their own permeability, a process that we have called Hb-induced Hb permeability. The magnitude of change of P DH is also related to Hb size. When PDH is corrected for the diffusive coefficient for each Hb species, no evidence of restricted diffusion is found. Immunofluorescent images demonstrate Hb-induced actin stress fiber formation and large intercellular gaps. These data provide the first quantitative assessment of the effect of polymerized HBOC on their own diffusion rates over time. We discuss the importance of these findings in terms of Hb extravasation rates, molecular sieving, and clinical consequences of HBOC use.albumin; blood substitutes; restricted diffusion HEMOGLOBIN (HB)-BASED O 2 carriers (HBOC) have received considerable attention as blood substitutes, and interest in developing these therapeutic macromolecules remains high, given the shortage and limited shelf-life of banked red blood cells, infection concerns, and, at times, unacceptable delays in crossmatching banked blood (1,24,26,33). Unfortunately, a number of unexpected problems have been associated with the use of HBOC, including extravasation, vasospasm, renal toxicity, and patient death (1,24,33). The ultimate utility of HBOC is to provide adequate oxygen delivery to patients requiring immediate resuscitation, as may occur following major trauma or surgical procedures associated with large-volume blood losses. Two untoward consequences of HBOC are extravasation of the HBOC itself, which is no longer able to participate in oxygen delivery, and the associated vasoconstriction due, at least in part, to local nitric oxide (NO) scavenging. The decrease in plasma Hb and localized vasospasms in the setting of anemia may create regional hypoxia. Overcoming these issues will...

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Effect of Vascular Endothelial Growth Factor on Cultured Endothelial Cell Monolayer Transport Properties

Cited by 113 publications

References 32 publications

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

Quantitative assessment of hemoglobin-induced endothelial barrier dysfunction

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