Faculty Opinions recommendation of Perinatal lethality and endothelial cell abnormalities in several vessel compartments of fibulin-1-deficient mice.

2001 ◽  
Author(s):  
Zena Werb
Keyword(s):  
Endothelial Cell ◽  
Perinatal Lethality ◽  
Deficient Mice

Abstract 48: Deletion of the Neuronal Guidance Molecule Epha2 Reduces Inflammation in Experimental Atherosclerosis

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Steven D Funk ◽  
Arif Yurdagul ◽  
Jonette Green ◽  
Patrick Albert ◽  
Marshall McInnis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Activation ◽  
Experimental Atherosclerosis ◽  
Marker Genes ◽  
Endothelial Cell Activation ◽  
Enhanced Expression ◽  
Guidance Molecule ◽  
Neuronal Guidance ◽  
Deficient Mice

Neuronal guidance molecules are increasingly implicated in inflammatory responses. Recently, our group demonstrated enhanced expression of the neuronal guidance molecule EphA2 and its ephrinA1 ligand in mouse and human atherosclerotic plaques, and elucidated a novel proinflammatory function for EphA2 perpetuating proinflammatory gene expression during endothelial cell activation. However, a direct role for Eph/ephrins in atherosclerosis has never been demonstrated. We now show that knocking out the EphA2 gene in Western diet-fed ApoE mice blunts atherosclerotic plaque location at multiple sites. This reduction in atherosclerosis is associated with decreased monocyte infiltration and diminished expression of proinflammatory genes. EphA2 reduction may affect monocyte homing through multiple mechanisms, since reducing EphA2 expression in cytokine-activated endothelial cells does not affect endothelial adhesion molecule expression or monocyte rolling but significantly decreases firm adhesion in primary human monocytes. Like endothelial cells, plaque macrophages also express EphA2, and macrophages derived from EphA2 deficient mice show diminished expression of M1 marker genes and enhanced expression of M2 marker genes compared to their ApoE counterparts. Surprisingly, EphA2 deficient mice show significantly elevated plasma cholesterol. However, this elevation does not involve increased LDL levels but instead occurs due to elevations in plasma HDL levels. Taken together, the current data suggest EphA2 inhibition results in a multifaceted protective effect on experimental atherosclerosis characterized by reduced endothelial cell activation, monocyte recruitment, and M1/M2 polarization and enhanced circulating HDL levels.

Superoxide mediates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules

2003 ◽  
Vol 284 (2) ◽  
pp. H535-H541 ◽  
Author(s):  
Wolfgang H. Cerwinka ◽  
Dianne Cooper ◽  
Christian F. Krieglstein ◽  
Chris R. Ross ◽  
Joe M. McCord ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Vascular System ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Induced Response ◽  
Wild Type ◽  
Binding Properties ◽  
Platelet Endothelial Cell Adhesion ◽  
Deficient Mice

Platelets have been implicated in the pathogenesis of different diseases of the vascular system, including atherosclerosis, sepsis, and ischemia-reperfusion injury; however, relatively little is known about the factors that regulate the interactions between circulating platelets and the vessel wall. The objective of this study was to define the contribution of superoxide to LPS-induced platelet-endothelial cell (P/E) adhesion in murine intestinal venules. The adhesion of rhodamine-6G-labeled murine platelets was monitored by intravital fluorescence microscopy. Four hours after LPS administration in control [wild-type (WT)] mice, an ∼10-fold increase in P/E adhesion was detected. This response did not result from LPS-induced platelet activation. The LPS-induced P/E adhesion was greatly attenuated in NAD(P)H oxidase-deficient mice and in WT mice rendered neutropenic with anti-neutrophil serum, whereas the response was unchanged in WT mice receiving a CD18 blocking MAb or in CD18-deficient mice. A chimeric form of MnSOD that exhibits the binding properties of extracellular SOD also attenuated the LPS-induced response in WT mice. These findings indicate that neutrophil-derived superoxide plays a major role in the modulation of endotoxin-induced P/E adhesion.

Effect of anti-oxidative enzyme gene-transfer on endothelial cell function of apolipoprotein-E deficient mice

2006 ◽  
Vol 45 (3) ◽  
pp. e73-e74
Author(s):  
P-J. Guns ◽  
T. Van Assche ◽  
W. Verreth ◽  
P. Fransen ◽  
B. Mackness ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Gene Transfer ◽  
Apolipoprotein E ◽  
Cell Function ◽  
Oxidative Enzyme ◽  
Endothelial Cell Function ◽  
Enzyme Gene ◽  
Deficient Mice

scholarly journals TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
James A Rickard ◽  
Holly Anderton ◽  
Nima Etemadi ◽  
Ueli Nachbur ◽  
Maurice Darding ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcriptional Activity ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Inflammatory Phenotype ◽  
Dependent Cell ◽  
Perinatal Lethality ◽  
Induced Apoptosis ◽  
Deficient Mice

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.

Molecular determinants of the prothrombogenic phenotype assumed by inflamed colonic venules

2005 ◽  
Vol 288 (5) ◽  
pp. G920-G926 ◽  
Author(s):  
Mikiji Mori ◽  
James W. Salter ◽  
Thorsten Vowinkel ◽  
Christian F. Krieglstein ◽  
Karen Y. Stokes ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Vascular Permeability ◽  
Leukocyte Adhesion ◽  
Colonic Inflammation ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Blocking Antibodies ◽  
Bone Marrow Chimeras ◽  
Temporally Correlated ◽  
Deficient Mice

Although platelets have been implicated in the pathogenesis of human inflammatory bowel diseases, little is known about the magnitude of platelet accumulation in the inflamed bowel, what regulates this process, and its relevance to the overall inflammatory response. In this study, intravital video microscopy was used to monitor the trafficking of platelets and leukocytes and vascular permeability in colonic venules during the development of colonic inflammation induced by 3% dextran sodium sulfate (DSS). Blocking antibodies directed against different adhesion molecules as well as P-selectin-deficient mice were used to define the adhesive determinants of DSS-induced platelet recruitment. DSS induced an accumulation of adherent platelets that was temporally correlated with the appearance of adherent leukocytes and with disease severity. Platelet adhesion and, to a lesser extent, leukocyte adhesion were attenuated by immunoblockade of P-selectin and its ligand P-selectin glycoprotein ligand-1 (PSGL-1), with contributions from both platelet- and endothelial cell-associated P-selectin. DSS induced a rapid and sustained increase in vascular permeability that was greatly attenuated in P-selectin-deficient mice. P-selectin bone marrow chimeras revealed that both endothelial cell- and platelet-associated P-selectin contribute to the P-selectin expression detected in the inflamed colonic microvasculature, with endothelial P-selectin making a larger contribution. Our findings indicate that colonic inflammation is associated with the induction of a prothrombogenic phenotype in the colonic microcirculation, with P-selectin and its ligand PSGL-1 playing a major role in the recruitment of platelets.

scholarly journals Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension

2016 ◽  
Vol 310 (3) ◽  
pp. L249-L262 ◽  
Author(s):  
Andrew J. Bryant ◽  
Ryan P. Carrick ◽  
Melinda E. McConaha ◽  
Brittany R. Jones ◽  
Sheila D. Shay ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Pulmonary Fibrosis ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial Cell ◽  
Tissue Growth ◽  
Vascular Endothelial ◽  
Pulmonary Vessel ◽  
Deficient Mice

Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.

C1 inhibitor prevents Gram-negative bacterial lipopolysaccharide-induced vascular permeability

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2350-2355 ◽  
Author(s):  
Dongxu Liu ◽  
Dong Zhang ◽  
Jennifer Scafidi ◽  
Xiao Wu ◽  
Cort C. Cramer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Multiple Organ Failure ◽  
Organ Failure ◽  
Vascular Permeability ◽  
Laser Scanning ◽  
Multiple Organ ◽  
C1 Inhibitor ◽  
Gram Negative ◽  
Deficient Mice

AbstractGram-negative bacterial endotoxemia may lead to the pathological increase of vascular permeability with systemic vascular collapse, a vascular leak syndrome, multiple organ failure (MOF), and/or shock. Previous studies demonstrated that C1 inhibitor (C1INH) protects mice from lipopolysaccharide (LPS)–induced lethal septic shock via a direct interaction with LPS. Here, we report that C1INH blocked the LPS-induced increase in transendothelial flux through an endothelial monolayer. In addition, LPS-mediated detachment of cultured endothelial cells was prevented with C1INH. C1INH also inhibited LPS-induced endothelial cell apoptosis as demonstrated by suppression of DNA fragmentation and annexin V expression. As illustrated by laser scanning confocal microscopy, C1INH completely blocked the binding of fluorescein isothiocyanate (FITC)–LPS to human umbilical vein endothelial cells (HUVECs). C1INH protected from localized LPS-induced increased plasma leakage in C57BL/6J mice and in C1INH-deficient mice. Local vascular permeability in response to LPS was increased to a greater extent in C1INH-deficient mice compared with wild-type littermate controls and was reversed by treatment with C1INH. Systemic administration of LPS to mice resulted in increased vascular permeability, which was reduced by C1INH. Therefore, these studies demonstrate that C1INH, in addition to its role in suppression of LPS-mediated macrophage activation, may play an important role in the prevention of LPS-mediated increased vascular permeability, endothelial cell injury, and multiple organ failure.

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