scholarly journals H2 S-donating sildenafil (ACS6) inhibits superoxide formation and gp91phox expression in arterial endothelial cells: role of protein kinases A and G

2008 ◽  
Vol 155 (7) ◽  
pp. 984-994 ◽  
Author(s):  
S Muzaffar ◽  
J Y Jeremy ◽  
A Sparatore ◽  
P Del Soldato ◽  
G D Angelini ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Kinases ◽  
Superoxide Formation ◽  
Arterial Endothelial Cells

Matrix Stiffening Induces a Pathogenic QKI-miR-7-SRSF1 Signaling Axis in Pulmonary Arterial Endothelial Cells

2021 ◽  
Author(s):  
Chen-Shan Chen Woodcock ◽  
Neha Hafeez ◽  
Adam Handen ◽  
Ying Tang ◽  
Lloyd D Harvey ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Rna Binding ◽  
Vascular Diseases ◽  
Vascular Stiffness ◽  
Artery Stiffness ◽  
Signaling Axis ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells ◽  
Splicing Factor 1

Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA binding protein Quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness up-regulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally up-regulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from PAH patients and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, while forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

Role of cadherins and plakoglobin in interendothelial adhesion under resting conditions and shear stress

1997 ◽  
Vol 273 (5) ◽  
pp. H2396-H2405 ◽  
Author(s):  
Hans-Joachim Schnittler ◽  
Bernd Püschel ◽  
Detlev Drenckhahn
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Time Course ◽  
Fluid Shear Stress ◽  
Vascular Endothelial ◽  
Fluid Shear ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1 ◽  
Arterial Endothelial Cells

The role of cadherins and the cadherin-binding cytosolic protein plakoglobin in intercellular adhesion was studied in cultured human umbilical venous endothelial cells exposed to fluid shear stress. Extracellular Ca2+depletion (<10−7 M) caused the disappearance of both cadherins and plakoglobin from junctions, whereas the distribution of platelet endothelial cell adhesion molecule 1 (PECAM-1) remained unchanged. Cells stayed fully attached to each other for several hours in low Ca2+ but began to dissociate under flow conditions. At the time of recalcification, vascular endothelial (VE) cadherin and β-catenin became first visible at junctions, followed by plakoglobin with a delay of ∼20 min. Full fluid shear stress stability of the junctions correlated with the time course of the reappearance of plakoglobin. Inhibition of plakoglobin expression by microinjection of antisense oligonucleotides did not interfere with the junctional association of VE-cadherin, PECAM-1, and β-catenin. The plakoglobin-deficient cells remained fully attached to each other under resting conditions but began to dissociate in response to flow. Shear stress-induced junctional dissociation was also observed in cultures of plakoglobin-depleted arterial endothelial cells of the porcine pulmonary trunk. These observations show that interendothelial adhesion under hydrodynamic but not resting conditions requires the junctional location of cadherins associated with plakoglobin. β-Catenin cannot functionally compensate for the junctional loss of plakoglobin, and PECAM-1-mediated adhesion is not sufficient for monolayer integrity under flow.

scholarly journals Role of mitogen-activated protein kinases in pulmonary endothelial cells exposed to cyclic strain

2000 ◽  
Vol 89 (6) ◽  
pp. 2391-2400 ◽  
Author(s):  
Hiroyuki Kito ◽  
Emery L. Chen ◽  
Xiujie Wang ◽  
Masataka Ikeda ◽  
Nobuyoshi Azuma ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Kinases ◽  
Cyclic Strain ◽  
Cell Alignment ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
Pulmonary Arterial ◽  
And Migration ◽  
Sb 203580

The aim of this study was to examine the role of mitogen-activated protein kinases (MAPKs) activation in bovine pulmonary arterial endothelial cells (EC) exposed to cyclic strain. EC were subjected to 10% average strain at 60 cycles/min. Cyclic strain induced activation of extracellular signal-regulated kinase (ERK; 1.5-fold), c-Jun NH2-terminal protein kinase (JNK; 1.9-fold), and p38 (1.5-fold) with a peak at 30 min. To investigate the functional role of the activated MAPKs, we analyzed cells after treatment with PD-98059, a specific ERK kinase inhibitor, or SB-203580, a catalytic inhibitor for p38, and after transient transfection with JNK(K-R), and MEKK(K-M) the respective catalytically inactive mutants of JNK1 and MAPK kinase kinase-1. Cyclic strain increased activator protein-1 (AP-1) binding activity, which was blocked by PD-98059 and SB-203580. Activity of AP-1-dependent luciferase reporter driven by 12- O-tetradecanoyl-phorbol-13-acetate-responsive element (TRE) was induced by cyclic strain, and this was attenuated by PD-98059, MEKK(K-M), JNK(K-R), and SB-203580. PD-98059 and SB-203850 did not inhibit cell alignment and migration induced by cyclic strain. MEKK(K-M) and JNK(K-R) transfection did not block cyclic strain-induced cell alignment. In conclusion, cyclic strain activates ERK, JNK, and p38, and their activation plays a role in transcriptional activation of AP-1/TRE but not in cell alignment and migration changes in bovine pulmonary arterial EC.

Role of AT1 and AT2 receptors in regulation of MAPKs and MKP-1 by ANG II in adult cardiac myocytes

1998 ◽  
Vol 275 (3) ◽  
pp. H906-H916 ◽  
Author(s):  
Thomas A. Fischer ◽  
Krishna Singh ◽  
Donald S. O’Hara ◽  
David M. Kaye ◽  
Ralph A. Kelly
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Ventricular Myocytes ◽  
Mrna Levels ◽  
Ang Ii ◽  
Terminal Protein ◽  
Erk Activity ◽  
Angiotensin Type

ANG II has been implicated in the hypertrophic response in ventricular myocytes by acting at the angiotensin type 1 (AT1) receptor. However, the role of the angiotensin type 2 (AT2) receptor in the adult heart is not as clearly understood. In adult rat ventricular myocytes (ARVM) and cardiac microvascular endothelial cells (CMEC), we examined the role of ANG II signaling, via AT1 and AT2 receptors, on the activation of the extracellular signal-regulated protein kinases (ERKs) and on the expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1. ANG II caused no detectable increase in ERK activity or in c- fos mRNA abundance in ARVM but increased ERK activity within 5 min in CMEC and increased c- fos mRNA levels. However, in the presence of the selective phosphoprotein phosphatase (PP-2A/PP-1) inhibitor okadaic acid (OA), a sustained increase in ERK activity, as well as in c- junNH2-terminal protein kinase activity, in ARVM was observed. ANG II increased MKP-1 mRNA levels within 15 min in ARVM and CMEC. In contrast to the response in endothelial cells, however, ANG II activation of MKP-1 in ARVM was mediated by AT2-receptor activation. Thus there is constitutive as well as inducible suppression of ERKs and c- junNH2-terminal protein kinases by MKP and PP-2A/PP-1 in the adult cardiac myocyte phenotype.

scholarly journals Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase Cδ

2010 ◽  
Vol 298 (1) ◽  
pp. L105-L116 ◽  
Author(s):  
Sanjiv Kumar ◽  
Neetu Sud ◽  
Fabio V. Fonseca ◽  
Yali Hou ◽  
Stephen M. Black
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Catalase Activity ◽  
Serine Phosphorylation ◽  
Nitric Oxide Signaling ◽  
Enos Uncoupling ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Previous studies have indicated that acute increases in shear stress can stimulate endothelial nitric oxide synthase (eNOS) activity through increased PI3 kinase/Akt signaling and phosphorylation of Ser1177. However, the mechanism by which shear stress activates this pathway has not been adequately resolved nor has the potential role of reactive oxygen species (ROS) been evaluated. Thus, the purpose of this study was to determine if shear-mediated increases in ROS play a role in stimulating Ser1177 phosphorylation and NO signaling in pulmonary arterial endothelial cells (PAEC) exposed to acute increases in shear stress. Our initial studies demonstrated that although shear stress did not increase superoxide levels in PAEC, there was an increase in H2O2 levels. The increases in H2O2 were associated with a decrease in catalase activity but not protein levels. In addition, we found that acute shear stress caused an increase in eNOS phosphorylation at Ser1177 phosphorylation and a decrease in phosphorylation at Thr495. We also found that the overexpression of catalase significantly attenuated the shear-mediated increases in H2O2, phospho-Ser1177 eNOS, and NO generation. Further investigation identified a decrease in PKCδ activity in response to shear stress, and the overexpression of PKCδ attenuated the shear-mediated decrease in Thr495 phosphorylation and the increase in NO generation, and this led to increased eNOS uncoupling. PKCδ overexpression also attenuated Ser1177 phosphorylation through a posttranslational increase in catalase activity, mediated via a serine phosphorylation event, reducing shear-mediated increases in H2O2. Together, our data indicate that shear stress decreases PKCδ activity, altering the phosphorylation pattern catalase, leading to decreased catalase activity and increased H2O2 signaling, and this in turn leads to increases in phosphorylation of eNOS at Ser1177 and NO generation.

scholarly journals Down‐regulation of BMP‐4 Expression in Coronary Arterial Endothelial Cells: Role of Shear Stress and the cAMP/PKA Pathway

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Anna Csiszar ◽  
Nazar Labinskyy ◽  
Kira E Smith ◽  
Aracelie Rivera ◽  
Erik N.T.P. Bakker ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Down Regulation ◽  
Pka Pathway ◽  
Arterial Endothelial Cells

The role of CXCL12 in the organ-specific process of artery formation

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3155-3161 ◽  
Author(s):  
Toshiaki Ara ◽  
Koji Tokoyoda ◽  
Rika Okamoto ◽  
Pandelakis A. Koni ◽  
Takashi Nagasawa
Keyword(s):  
Endothelial Cells ◽  
Small Intestine ◽  
B Lymphopoiesis ◽  
Capillary Plexus ◽  
Organ Specific ◽  
Chemokine Ligand ◽  
Stromal Cell Derived Factor ◽  
Primary Capillary Plexus ◽  
Arterial Endothelial Cells

AbstractCXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1 [SDF-1]/pre-B-cell growth-stimulating factor [PBSF]) and its receptor CXCR4 are essential for vascularization in the gastrointestinal tract as well as B lymphopoiesis and colonization of bone marrow by hematopoietic cells. However, the mechanism by which CXCL12/CXCR4 functions in blood vessel formation remains elusive. Here, we have found a novel mode of organ vascularization and determined the roles of CXCL12 in these processes. In the developing small intestine, many short interconnecting vessels form between larger superior mesenteric artery (SMA) and the neighboring primary capillary plexus surrounding the primitive gut, and they elongate and become the arteries supplying the small intestine. Mice lacking CXCL12 or CXCR4 lack the interconnecting vessels but have normal venous networks. The mutants lack filopodial extension and intussusception from endothelial cells of SMAs seen in wild-type embryos. CXCR4 is specifically expressed in arteries in the developing mesenteries and its expression is severely reduced in CXCL12–/– embryos. Mice in which CXCR4 is specifically deleted in the endothelium reveal vascular defects identical to those observed in the conventional CXCR4–/– embryos. Together, CXCL12 acts on arterial endothelial cells of SMA to up-regulate CXCR4 and mediate the connection between the larger artery and neighboring capillary plexus in an organ-specific manner.

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