Arteriosclerosis, Thrombosis, and Vascular Biology
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Intercellular Transport of MicroRNAs Extracellular microRNAs (miRNA) are present in most biological fluids, relatively stable, and hold great potential for disease biomarkers and novel therapeutics. Circulating miRNAs are transported by membrane-derived vesicles (exosomes and microparticles), lipoproteins, and other ribonucleoprotein complexes. Evidence suggests that miRNAs are selectively exported from cells with distinct signatures that have been found to be altered in many pathophysiologies, including cardiovascular disease. Protected from plasma ribonucleases by their carriers, functional miRNAs are delivered to recipient cells by various routes. Transferred miRNAs use cellular machinery to reduce target gene expression and alter cellular phenotype. Similar to soluble factors, miRNAs mediate cell-to-cell communication linking disparate cell types, diverse biological mechanisms, and homeostatic pathways. Although significant advances have been made, miRNA intercellular communication is full of complexities and many questions remain. This review brings into focus what is currently known and outstanding in a novel field of study with applicability to cardiovascular disease.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 33 Số 2 - Trang 186-192 - 2013
Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis
Objective—
Previously, we have identified bone morphogenetic protein endothelial cell precursor–derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project, we now investigate how BMPER acts in concert with key molecules of angiogenesis to promote blood vessel formation.
Approach and Results—
To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Additionally, FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by subcutaneous Matrigel injections with and without bFGF in C57BL/6_Bmper
+/−
mice. Aortic ring assays of C57BL/6_Bmper
+/−
mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor.
Conclusions—
Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 35 Số 2 - Trang 358-367 - 2015
Micromanaging Vascular Smooth Muscle Cell Differentiation and Phenotypic Modulation The phenotype of vascular smooth muscle cells (VSMCs) is dynamically regulated in response to various stimuli. In a cellular process known as phenotype switching, VSMCs alternate between a contractile and synthetic phenotype state. Deregulation of phenotype switching is associated with vascular disorders such as atherosclerosis, restenosis after angioplasty, and pulmonary hypertension. An important role for microRNAs (miRNAs) in VSMC development and phenotype switching has recently been uncovered. Individual miRNAs are involved in promoting both contractile and synthetic VSMC phenotype. In this review, we summarize recent advances in the understanding of miRNA function in the regulation of VSMC phenotype regulation.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 31 Số 11 - Trang 2370-2377 - 2011
Increased Proangiogenic Activity of Mobilized CD34 <sup>+</sup> Progenitor Cells of Patients With Acute ST-Segment–Elevation Myocardial Infarction
Objective—
Proangiogenic effects of mobilized bone marrow–derived stem/progenitor cells are essential for cardiac repair after myocardial infarction. MicroRNAs (miRNA/miR) are key regulators of angiogenesis. We investigated the differential regulation of angio-miRs, that is, miRNAs regulating neovascularization, in mobilized CD34
+
progenitor cells obtained from patients with an acute ST-segment–elevation myocardial infarction (STEMI) as compared with those with stable coronary artery disease or healthy subjects.
Approach and Results—
CD34
+
progenitor cells were isolated from patients with STEMI (on day 0 and day 5), stable coronary artery disease, and healthy subjects (n=27). CD34
+
progenitor cells of patients with STEMI exhibited increased proangiogenic activity as compared with CD34
+
cells from the other groups. Using a polymerase chain reaction–based miRNA-array and real-time polymerase chain reaction validation, we identified a profound upregulation of 2 known angio-miRs, that are, miR-378 and let-7b, in CD34
+
cells of patients with STEMI. Especially, we demonstrate that miR-378 is a critical regulator of the proangiogenic capacity of CD34
+
progenitor cells and its stimulatory effects on endothelial cells in vitro and in vivo, whereas let-7b upregulation in CD34
+
cells failed to proof its effect on endothelial cells in vivo.
Conclusions—
The present study demonstrates a significant upregulation of the angio-miRs miR-378 and let-7b in mobilized CD34
+
progenitor cells of patients with STEMI. The increased proangiogenic activity of these cells in patients with STEMI and the observation that in particular miR-378 regulates the angiogenic capacity of CD34
+
progenitor cells in vivo suggest that this unique miRNA expression pattern represents a novel endogenous repair mechanism activated in acute myocardial infarction.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 37 Số 2 - Trang 341-349 - 2017
PECAM-1: A Multi-Functional Molecule in Inflammation and Vascular Biology Platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) is a molecule expressed on all cells within the vascular compartment, being expressed to different degrees on most leukocyte sub-types, platelets, and on endothelial cells where its expression is largely concentrated at junctions between adjacent cells. As well as exhibiting adhesive properties, PECAM-1 is an efficient signaling molecule and is now known to have diverse roles in vascular biology including roles in angiogenesis, platelet function, and thrombosis, mechanosensing of endothelial cell response to fluid shear stress, and regulation of multiple stages of leukocyte migration through venular walls. This review will focus on some new developments with respect to the role of PECAM-1 in inflammation and vascular biology, highlighting the emerging complexities associated with the functions of this unique molecule.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 27 Số 12 - Trang 2514-2523 - 2007
Intercellular Adhesion Molecule 1 Engagement Modulates Sphingomyelinase and Ceramide, Supporting Uptake of Drug Carriers by the Vascular Endothelium
Objective—
Engagement of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells by ICAM-1-targeted carriers induces cell adhesion molecule–mediated endocytosis, providing intraendothelial delivery of therapeutics. This pathway differs from classical endocytic mechanisms and invokes aspects of endothelial signaling during inflammation. ICAM-1 interacts with Na
+
/H
+
exchanger NHE1 during endocytosis, but it is unclear how this regulates plasmalemma and cytoskeletal changes. We studied such aspects in this work.
Methods and Results—
We used fluorescence and electron microscopy, inhibitors and knockout tools, cell culture, and mouse models. ICAM-1 engagement by anti-ICAM carriers induced sphingomyelin-enriched engulfment structures. Acid sphingomyelinase (ASM), an acidic enzyme that hydrolyzes sphingomyelin into ceramide (involved in plasmalemma deformability and cytoskeletal reorganization), redistributed to ICAM-1-engagement sites at ceramide-enriched areas. This induced actin stress fibers and carrier endocytosis. Inhibiting ASM impaired ceramide enrichment, engulfment structures, cytoskeletal reorganization, and carrier uptake, which was rescued by supplying this enzyme activity exogenously. Interfering with NHE1 rendered similar outcomes, suggesting that Na
+
/H
+
exchange might provide an acidic microenvironment for ASM at the plasmalemma.
Conclusion—
These findings are consistent with the ability of endothelial cells to internalize relatively large ICAM- 1--targeted drug carriers and expand our knowledge on the regulation of the sphingomyelin/ceramide pathway by the vascular endothelium.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 32 Số 5 - Trang 1178-1185 - 2012
Signal Transduction Pathways Mediated by PECAM-1 Recent studies of platelet endothelial cell adhesion molecule-1 (PECAM-1 [CD31])-deficient mice have revealed that this molecule plays an important role in controlling the activation and survival of cells on which it is expressed. In this review, we focus on the complex cytoplasmic domain of PECAM-1 and describe what is presently known about its structure, posttranslational modifications, and binding partners. In addition, we summarize findings that implicate PECAM-1 as an inhibitor of cellular activation via protein tyrosine kinase–dependent signaling pathways, an activator of integrins, and a suppressor of cell death via pathways that depend on damage to the mitochondria. The challenge of future research will be to bridge our understanding of the functional and biochemical properties of PECAM-1 by establishing mechanistic links between signals transduced by the PECAM-1 cytoplasmic domain and discrete cellular responses.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 23 Số 6 - Trang 953-964 - 2003
MicroRNA-155 Deficiency Results in Decreased Macrophage Inflammation and Attenuated Atherogenesis in Apolipoprotein E–Deficient Mice
Objective—
microRNA-155 (miR155) plays a critical role in immunity and macrophage inflammation. We aim to investigate the role of miR155 in atherogenesis.
Approach and Results—
Quantitative real-time polymerase chain reaction showed that miR155 was expressed in mouse and human atherosclerotic lesions. miR155 expression in macrophages was correlated positively with proinflammatory cytokine expression. Lentivirus-mediated overexpression of miR155 in macrophages enhanced their inflammatory response to lipopolysaccharide through targeting suppressor of cytokine signaling-1 and impaired cholesterol efflux from acetylated low-density lipoprotein–loaded macrophages, whereas deficiency of miR155 blunted macrophage inflammatory responses and enhanced cholesterol efflux possibly via enhancing lipid loading–induced macrophage autophagy. We next examined the atherogenesis in apolipoprotein E–deficient (apoE
−/−
) and miR155
−/−
/apoE
−/−
(double knockout) mice fed a Western diet. Compared with apoE
−/−
mice, the double knockout mice developed less atherosclerosis lesion in aortic root, with reduced neutral lipid content and macrophages. Flow cytometric analysis showed that there were increased number of regulatory T cells and reduced numbers of Th17 cells and CD11b+/Ly6C
high
cells in the spleen of double knockout mice. Peritoneal macrophages from the double knockout mice had significantly reduced proinflammatory cytokine expression and secretion both in the absence and presence of lipopolysaccharide stimulation. To determine whether miR155 in leukocytes contributes to atherosclerosis, we performed a bone marrow transplantation study. Deficiency of miR155 in bone marrow–derived cells suppressed atherogenesis in apoE
−/−
mice, demonstrating that hematopoietic cell–derived miR155 plays a critical role.
Conclusions—
miR155 deficiency attenuates atherogenesis in apoE
−/−
mice by reducing inflammatory responses of macrophages, enhancing macrophage cholesterol efflux and resulting in an antiatherogenic leukocyte profile. Targeting miR155 may be a promising strategy to halt atherogenesis.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 34 Số 4 - Trang 759-767 - 2014
Vascular Protection
Abstract
—There is widespread interest in the use of the angiogenic cytokine, vascular endothelial growth factor (VEGF), for the treatment of cardiovascular disease. The main paradigm for VEGF cardiovascular therapy is the stimulation of “therapeutic angiogenesis” in ischemic myocardial and peripheral vascular limb disease. In this review, approaches to VEGF therapy based on the therapeutic angiogenesis model are critically assessed, and the alternative mechanism of vascular protection is advanced. Vascular protection is defined as the VEGF-induced enhancement of endothelial functions that mediate the inhibition of vascular smooth muscle cell proliferation, enhanced endothelial cell survival, suppression of thrombosis, and anti-inflammatory effects. VEGF-induced synthesis of NO and prostacyclin are both likely to be key mediators of VEGF-dependent vascular protection. Investigation into vascular protection should help us to gain insight into the underlying mechanisms of the cardiovascular actions of VEGF and should prove valuable in the development of novel therapeutic approaches based on local VEGF gene delivery.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 20 Số 6 - Trang 1512-1520 - 2000
VEGF Protects Against Oxidized LDL Toxicity to Endothelial Cells by an Intracellular Glutathione-Dependent Mechanism Through the KDR Receptor
Abstract
—Although the accumulation of vascular endothelial growth factor (VEGF) has been observed in human atherosclerotic lesions, the exact role of this growth factor in atherogenesis remains unknown. We hypothesized that VEGF in the vascular wall might have a preventive effect on endothelial cell damage during atherosclerosis. To test our hypothesis, we examined whether VEGF protects against the toxicity of oxidized low density lipoprotein (Ox-LDL) in cultured endothelial cells derived from bovine aortas (BAECs). Preincubation of BAECs with VEGF prevented Ox-LDL–induced toxicity in a preincubation time– and VEGF concentration–dependent manner. Addition of
N
ω
-nitro-
l
-arginine methyl ester, a nitric oxide synthase inhibitor, did not reverse the protective effect of VEGF on Ox-LDL toxicity. Incubation of BAECs with VEGF increased intracellular glutathione (GSH) content in a time-dependent manner. Combined addition of VEGF and
l
-buthionine sulfoximine, a GSH synthesis inhibitor, reversed both GSH levels and the protective effect of VEGF on Ox-LDL–induced cytotoxicity. Placenta growth factor, which ligates to the VEGF Flt-1 receptor but not KDR/Flk-1, failed to prevent Ox-LDL toxicity and had no effect on intracellular GSH levels. An anti-KDR antibody completely blocked these beneficial activities of VEGF. These results suggest that VEGF prevents Ox-LDL–induced endothelial cell damage via an intracellular GSH-dependent mechanism through the KDR/Flk-1 receptor.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 21 Số 5 - Trang 765-770 - 2001
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