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Vascular remodeling alters adhesion protein and cytoskeleton reactions to inflammatory stimuli resulting in enhanced permeability increases in rat venules.

ABSTRACT: Vascular remodeling has been implicated in many inflammation-involved diseases. This study aims to investigate the microvascular remodeling-associated alterations in cell-cell adhesion and cytoskeleton reactions to inflammatory stimuli and their impact on microvessel permeability. Experiments were conducted in individually perfused rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp), and endothelial intracellular calcium concentration, [Ca(2+)](i), was measured in fura-2-perfused vessels. Alterations in VE-cadherin and F-actin arrangement were examined by confocal imaging. Vascular wall cellular composition and structural changes were evaluated by electron microscopy. Vessels exposed to platelet activating factor (PAF) on day 1 were reevaluated 3 days later in rats that had undergone survival surgery. Initial PAF exposure and surgical disturbance increased microvascular wall thickness along with perivascular cell proliferation and altered F-actin arrangement. Although basal permeability was not changed, upon reexposure to PAF, peak endothelial [Ca(2+)](i) was augmented and the peak Lp was 9.3 ± 1.7 times higher than that of day 1. In contrast to patterns of PAF-induced stress fiber formation and VE-cadherin redistribution observed in day 1 vessels, the day 4 vessels at the potentiated Lp peak exhibited wide separations of VE-cadherin between endothelial cells and striking stress fibers throughout the vascular walls. Confocal images and ultrastructural micrographs also revealed that the largely separated VE-cadherin and endothelial gaps were completely covered by F-actin bundles in extended pericyte processes at the PAF-induced Lp peak. These results indicate that inflammation-induced vascular remodeling increased endothelial susceptibility to inflammatory stimuli with augmented Ca(2+) response resulting in upregulated contractility and potentiated permeability increase. Weakened adhesions between the endothelial cells and contractile mechanisms are both involved in increasing permeability in the intact microvessels and are aggravated during remodeling. The perivascular cells play important roles in stabilizing the microvessel wall, while lessening an otherwise much greater magnitude of leakage during cytoskeletal contraction.

SUBMITTER: Yuan D

PROVIDER: S-EPMC3487498 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Vascular remodeling alters adhesion protein and cytoskeleton reactions to inflammatory stimuli resulting in enhanced permeability increases in rat venules.

Yuan Dong D He Pingnian P

Journal of applied physiology (Bethesda, Md. : 1985) 20120726 7

Vascular remodeling has been implicated in many inflammation-involved diseases. This study aims to investigate the microvascular remodeling-associated alterations in cell-cell adhesion and cytoskeleton reactions to inflammatory stimuli and their impact on microvessel permeability. Experiments were conducted in individually perfused rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp), and endothelial intracellular calcium concentration, [Ca(2+) ...[more]

PMID: 22837164

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Project description:BackgroundMicrocirculatory disturbance is closely associated with multiple diseases such as ischemic and septic stroke. Luteolin (3,4,5,7-tetrahydroxyflavone) is a vascular protective flavonoid present in several dietary foods. However, how luteolin plays a role in microcirculatory disturbance is still unknown. The purpose of this study was to find out the influence of luteolin on the lipopolysaccharide (LPS)-induced microcirculatory disturbance, focusing on its effect on leukocyte adhesion and the underlying mechanism of this effect.MethodsAfter injecting LPS into rats, we used an inverted intravital microscope to observe the velocity of red blood cells in venules, numbers of leukocytes adherent to and emigrated across the venular wall, hydrogen peroxide production in venular walls and mast cell degranulation. Intestinal microcirculation blood flow was measured by High-resolution Laser Doppler Perfusion Imaging. Histological changes of small intestine and mesenteric arteries were evaluated. Additionally, cell adhesion stimulated by LPS was tested on EA.hy926 and THP-1 cells. The production of pro-inflammatory cytokines, adhesion molecules and the activation of TLR4/Myd88/NF-κB signaling pathway were determined.ResultsThe results showed luteolin significantly inhibited LPS-induced leukocyte adhesion, hydrogen peroxide production and mast cell degranulation, and increased intestinal microcirculation blood flow and ameliorated pathological changes in the mesenteric artery and the small intestine. Furthermore, luteolin inhibited the release of pro-inflammatory cytokines, the expression of TLR4, Myd88, ICAM-1, and VCAM-1, the phosphorylation of IκB-α and NF-κB/p65 in LPS stimulated EA.hy926.ConclusionsOur findings revealed that it is likely that luteolin can ameliorate microcirculatory disturbance. The inhibitory effects of luteolin on the leukocyte adhesion stimulated by LPS, which participates in the development of microcirculatory disturbance, are mediated through the regulation of the TLR4/Myd88/NF-κB signaling pathway.

Project description:Pathologically increased vascular permeability is an important dysfunction in the pathomechanism of life-threatening conditions, such as sepsis, ischemia/reperfusion, or hereditary angioedema (HAE), diseases accompanied by uncontrolled activation of the complement system. HAE for example is caused by the deficiency of C1-inhibitor (the main regulator of early complement activation), which leads to edematous attacks threatening with circulatory collapse. We have previously reported that endothelial cells become activated during HAE attacks. A natural target of C1-inhibitor is mannan-binding lectin-associated serine protease-1 (MASP-1), a multifunctional serine protease, which plays a key role in the activation of complement lectin pathway. We have previously shown that MASP-1 induces the pro-inflammatory activation of endothelial cells and in this study we investigated whether MASP-1 can directly affect endothelial permeability. All experiments were performed on human umbilical vein endothelial cells (HUVECs). Real-time micro electric sensing revealed that MASP-1 decreases the impedance of HUVEC monolayers and in a recently developed permeability test (XperT), MASP-1 dose-dependently increased endothelial paracellular transport. We show that protease activated receptor-1 mediated intracellular Ca2+-mobilization, Rho-kinase activation dependent myosin light chain (MLC) phosphorylation, cytoskeletal actin rearrangement, and disruption of interendothelial junctions are underlying this phenomenon. Furthermore, in a whole-transcriptome microarray analysis MASP-1 significantly changed the expression of 25 permeability-related genes in HUVECs-for example it up-regulated bradykinin B2 receptor expression. According to our results, MASP-1 has potent permeability increasing effects. During infections or injuries MASP-1 may help eliminate the microbes and/or tissue debris by enhancing the extravasation of soluble and cellular components of the immune system, however, it may also play a role in the pathomechanism of diseases, where edema formation and complement lectin pathway activation are simultaneously present. Our findings also raise the possibility that MASP-1 may be a promising target of anti-edema drug development.

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Vascular remodeling alters adhesion protein and cytoskeleton reactions to inflammatory stimuli resulting in enhanced permeability increases in rat venules.

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Vascular remodeling alters adhesion protein and cytoskeleton reactions to inflammatory stimuli resulting in enhanced permeability increases in rat venules.

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