PubMed Health⌕ Search

Biomedical subjects

A Tedgui

Publications and source records attributed to A Tedgui.

At least 19 recordsLinked to original sources
PubMed2006

Characterization of neointima lesions associated with arteriovenous fistulas in a mouse model.

Arteriovenous fistulas (AVFs) are usually used for vascular access in the provision of hemodialysis, but AVFs have a 1-year patency rate of only about 60% owing to stenosis. As the molecular mechanisms behind AVF neointimal hyperplasia remain largely unknown, representative models in transgenic mice could be useful to study this process at the genetic level. Hence, we characterized neointimal lesion formation in a model of AVF recently developed in the mouse, where the common carotid artery was end-to-side sutured to jugular vein in C57BL/6J mice. At the site of anastomosis, arterial wall thickening was observed as early as 1 week after surgery (fourfold) and progressed to six- and 10-fold original thickness in carotid arteries after 2 and 3 weeks, respectively. The lumen of the carotid artery was significantly narrowed owing to neointima hyperplasia, and thrombosis was observed in the vein wall opposite to the anastomosed artery. Histological and immunohistochemical analyses revealed that 3-week neointimal lesions consisted of abundant smooth muscle cells (alpha-actin(+)) and a small number of membrane attack complex-1+ macrophages. Furthermore, using chimeric mice receiving bone marrow from transgenic mice expressing the LacZ gene in smooth muscle (SM-LacZ), it was found that bone marrow stem cells did not contribute to smooth muscle cell accumulation in neointimal lesions of AVF arteries. Thus, this model, which reproduces many of the features of human AVF, should prove useful for our understanding of the mechanism of neointimal formation and to evaluate the effects of drugs and gene therapy on this disease.

Animals↗
PubMed2006

Molecular mechanisms of the vascular responses to haemodynamic forces.

Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow and shear stress. Significant variations in mechanical forces, of physiological or physiopathological nature, occur in vivo. These are accompanied by phenotypical modulation of smooth muscle cells and endothelial cells, producing structural modifications of the arterial wall. In all the cases, vascular remodelling can be allotted to a modification of the tensional strain or shear, and underlie a trend to reestablish baseline mechanical conditions. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Mechanical forces also initiate complex signal transduction cascades, including nuclear factor-kappaB and mitogen-activated protein kinase pathways, leading to functional changes within the cell.

Animals↗
PubMed2004

In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: a clue to the understanding of the mechanisms of thrombotic plaque erosion.

BACKGROUND: The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. METHODS AND RESULTS: Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43+/-0.30 versus 0.93+/-0.44, respectively; P=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (P<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P=0.04). These results were confirmed in balloon-injured atheromatous arteries. CONCLUSIONS: In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Circulating procoagulant microparticles and soluble GPV in myocardial infarction treated by primary percutaneous transluminal coronary angioplasty. A possible role for GPIIb-IIIa antagonists.

Circulating procoagulant microparticles (MP) were measured as markers of vascular damage and prothrombotic risk in patients undergoing ST-segment myocardial infarction (STEMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) and additional GPIIb-IIIa antagonists. Cells possibly more responsive to GPIIb-IIIa (alpha(IIb)beta(3)) antagonists were evidenced through MP phenotypes by comparison with healthy volunteers (HV) and STEMI patients treated by PTCA without GPIIb-IIIa antagonist (CP). In 50 STEMI patients, blood samples were collected at day 1 and day 6. Circulating procoagulant MP were captured on annexin V and quantified by prothrombinase assay as nanomolar phosphatidylserine equivalents (nm PhtdSer). Platelet activation by thrombin was confirmed through independent measurement of soluble GPV (sGPV). With respect to HV, procoagulant MP levels were high in patients with STEMI or unstable angina, platelet-derived MP and elevated sGPV testifying to significant platelet activation. A substantial release of endothelial-derived MP was evidenced simultaneously. In abciximab-treated patients, procoagulant MP, mainly of platelet origin, decreased precociously at day 1 (4.2 +/- 0.6 vs. CP 15.5 +/- 2.1 nm PhtdSer; P = 0.001) together with sGPV (36 +/- 3 vs. CP 58 +/- 8 ng mL(-1); P = 0.02). Leukocyte-derived MP decreased at day 6 (0.12 +/- 0.04 vs. CP 0.56 +/- 0.12 nm PhtdSer; P = 0.01) suggesting a possible effect on underlying inflammatory status. In patients presenting cardiovascular events at 6-month follow-up, procoagulant MP levels at day 1 could be indicative of a worsened outcome. MP could constitute a relevant parameter for the follow-up of STEMI patients treated by GPIIb-IIIa antagonists.

Abciximab↗
PubMed2004

[Physiopathology of atherosclerosis in diabetics].

Vascular diseases, especially atherosclerosis, are the main cause of morbidity and mortality in diabetics. Diabetes greatly increases the risk of developing coronary heart disease, cerebral vascular accident and lower limb arteritis. The physiopathology of vascular disease in the diabetic patient involves endothelial and smooth muscle cell abnormalities. Metabolic disturbances which are characteristic of diabetes, such as hyperglycaemia or AGE accumulation, contribute to endothelial dysfunction and augment the inflammatory response at the vascular level. Atherosclerotic plaques in diabetics are more inflammatory than in non-diabetics, with an accumulation of macrophages and T lymphocytes, a larger lipid core and the presence of a greater number of macrophages and smooth muscle cells in apoptosis, which makes them more vulnerable.

Arteriosclerosis↗
PubMed2003

Protective role of uncoupling protein 2 in atherosclerosis.

BACKGROUND: Uncoupling protein 2 (UCP2) regulates the production of reactive oxygen species in macrophages. However, its role in atherosclerosis is unknown. METHODS AND RESULTS: Irradiated low-density lipoprotein receptor deficient mice (LDLR-/-) were transplanted with bone marrow from either UCP2 deficient mice (Ucp2-/-) or wild type mice (Ucp2+/+). Mice were fed an atherogenic diet for 7 weeks. Engraftment of bone marrow cells was confirmed by the presence of UCP2 protein expression in spleen cell mitochondria of Ucp2+/+ transplanted mice and its absence in Ucp2-/- transplanted mice. Leukocyte counts and plasma cholesterol levels were comparable in both groups. We found a marked increase in atherosclerotic lesion size in the thoracic aorta of Ucp2-/- transplanted mice compared with control Ucp2+/+ transplanted mice (8.3+/-0.9% versus 4.3+/-0.4%, respectively; P<0.005), as well as in the aortic sinus (150 066+/-12 388 microm2 versus 105 689+/-9 727 microm2, respectively; P<0.05). This was associated with increased nitrotyrosine staining, which suggests enhanced oxidative stress. Analysis of plaque composition revealed a significant increase in macrophage accumulation (P<0.05) and apoptosis (P<0.05), along with a decrease in collagen content (P<0.05), suggesting a potentially more vulnerable phenotype. CONCLUSION: These results suggest a protective role for UCP2 against atherosclerosis.

Animals↗
PubMed2003

The atheroprotective effect of 17 beta-estradiol is not altered in P-selectin- or ICAM-1-deficient hypercholesterolemic mice.

The mechanisms that mediate the atheroprotective properties of estrogens remain obscure. In the present study, we evaluated the involvement of the adhesion molecule P-selectin, intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) in the atheroprotective effect of estrogens in murine models evaluating early steps of atherosclerosis. First, we studied the effect of 17 beta-estradiol (E2) administration for 12 weeks on fatty streak constitution at the root aorta of ovariectomized female mice deficient in apolipoprotein E (apoE) alone or deficient in both apoE and either P-selectin or ICAM-1. Compared with respective placebo groups, E2 significantly prevented the development of fatty streak, to a similar extent in all three genotypes (-70.0% in apoE(-/-), -77.4% in apoE(-/-) P-selectin(-/-), and -77.1% in apoE(-/-) ICAM-1(-/-)). Second, the endothelial expression of VCAM-1 at the root aorta was assessed by immunohistochemistry in either placebo or E2-treated ovariectomized C57BL/6 female mice fed an atherogenic diet. Compared with placebo, E2 treatment resulted in a 31.8% decrease of VCAM-1 endothelial expression at this lesion-prone site (P=0.03). These results demonstrate that P-selectin and ICAM-1 are not involved in the atheroprotective effect of estrogens, and suggest that VCAM-1 could play a role in this process.

Animals↗
PubMed2003

Apoptosis, a major determinant of atherothrombosis.

Clinical manifestations of atherosclerosis are the consequences of atherosclerotic plaque rupture which triggers thrombus formation. Tissue factor (TF) is a key element in the initiation of the coagulation cascade and is crucial in thrombus formation following plaque disruption. TF activity is highly dependent on the presence of phosphatidylserine (PS), an anionic phospholipid that is redistributed on the cell surface during apoptotic death conferring a potent procoagulant activity to the apoptotic cell. Apoptosis occurs in the human atherosclerotic plaque, and shed membrane apoptotic microparticles rich in PS are produced in considerable amounts within the lipid core. These microparticles carry almost all TF activity and are responsible for the procoagulant activity of the plaque. Moreover, luminal endothelial cell apoptosis might be responsible for thrombus formation on eroded plaques without rupture. Apoptosis might also play a major role in blood thrombogenicity via circulating procoagulant microparticles that are found at high levels in patients with acute coronary syndromes.

Apoptosis↗
PubMed2003

[Neurosurgical embryology. Part 8: Post-natal angiogenesis and remodeling].

Post-natal angiogenesis (microvascular proliferation) and remodeling (modifications of diameter and wall thickness) occur in various physiological circumstances including adaptation to exercise or wound healing. The formation of a new vessel is submitted to the combinative action of growth factors. New endothelial cells migrate, proliferate, differentiate and attract pericytes and future smooth muscle cells to create the new vessel. Powerful stimuli leading to remodeling and to the creation of new vessels are mainly represented by hemodynamic forces generated by pressure and blood flow, and by hypoxia. Our purpose is to overview the molecular mechanisms and the stimuli giving rise to these processes.

Animals↗
PubMed2003

[Inflammation and atherosclerosis].

Atherosclerosis is a vascular pathology in which inflammation plays a major role at every stage of the disease. The inflammatory process develops in response to abnormal cholesterol deposits in the intima of large arteries. The inflammatory reaction is initiated by a phase of endothelial activation induced by cytokines, oxidized low density lipoprotein (LDL) and/or changes in endothelial shear stress. This leads to the primary expression of endothelial adhesion molecules and chemokines followed by the recruitment and activation of circulating monocytes and lymphocytes. The clinical manifestations of atherosclerosis, including acute coronary syndromes, are the consequences of atherosclerotic plaque rupture/erosion that triggers thrombus formation leading to the occlusion of the vessel lumen. The local inflammatory process at the level of the atherosclerotic plaque might influence the stability of the plaque through its potential effects on the extracellular matrix, and on the plaque thrombogenicity. In humans, systemic inflammation has been recognized as a major risk factor of occurrence of acute coronary syndromes.

Arteriosclerosis↗
PubMed2002

Oncostatin M induces procoagulant activity in human vascular smooth muscle cells by modulating the balance between tissue factor and tissue factor pathway inhibitor.

Oncostatin M (OSM) is a cytokine of the interleukin-6 (IL-6) family secreted by activated monocytes, and is expressed in atherosclerotic plaque. Smooth muscle cells (SMC), by expressing tissue factor (TF) and tissue factor pathway inhibitor (TFPI) can contribute to the thrombogenicity of atherosclerotic plaque. Consequently, the aim of this study was to evaluate the effects of OSM on the procoagulant activity of SMC. We observed that OSM induced in a concentration-dependent manner a potent procoagulant activity (PCA) that was related in part to an increased synthesis of TF, both at the cell membrane and in SMC lysates. The increased expression of TF on SMC membrane induced by OSM was sustained and was still observed 24 h after stimulation by OSM. IL-6 and leukaemia inhibitory factor (LIF), two OSM-related cytokines, did not significantly modify TF expression at the surface of SMC. In addition to its effects on TF, OSM decreased the secretion of TFPI in the supernatants of SMC, as well as in the lysates, but was devoid of effect on TFPI bound at the membrane of SMC. IL-6 and LIF reduced also TFPI secretion, which could explain why the PCA of SMC lysates treated by IL-6 or LIF was increased, despite an absence of effect on TF expression. In conclusion, these data support the hypothesis that by increasing the PCA of SMC, OSM might be involved in the thrombotic complications associated with plaque rupture.

Aorta↗
PubMed2002

Increased plasma concentrations of interleukin-18 in acute coronary syndromes.

OBJECTIVE: To examine the relation between plasma concentrations of interleukin-18 (IL-18), the interferon gamma inducing factor, and clinical instability of coronary artery disease. DESIGN AND SETTING: Observational study in a university hospital. PATIENTS: 11 patients with unstable angina and negative troponin I, 21 patients with acute non-Q wave myocardial infarction (MI), 21 patients with acute Q wave MI, 9 patients with stable angina, and 11 controls. MAIN OUTCOME MEASURES: Plasma IL-18 concentrations and their relation to clinical instability and myocardial dysfunction. RESULTS: Plasma concentrations of IL-18 were significantly increased in the unstable angina and MI groups in comparison with the stable angina and control groups (p < 0.01). No difference in IL-18 concentrations were found between patients with unstable angina, patients with non-Q wave MI, and patients with Q wave MI. Plasma IL-18 concentrations significantly correlated with decreased left ventricular ejection fraction (p = 0.01). CONCLUSIONS: Plasma IL-18 concentrations are increased in patients with acute coronary syndromes and correlate with the severity of myocardial dysfunction.

Acute Disease↗
PubMed2001

Increased ischemia-induced angiogenesis in the staggerer mouse, a mutant of the nuclear receptor Roralpha.

Ror alpha is an orphan nuclear receptor. In homozygous staggerer mutant mice (Ror alpha(sg/sg)), a deletion within the Ror alpha gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Ror alpha in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Ror alpha(+/+) and Ror alpha(sg/sg) mice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Ror alpha(sg/sg) mice and in Ror alpha(+/+) littermates. Conversely, at day 28, Ror alpha(sg/sg) mice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Ror alpha(sg/sg) mice (0.83+/-0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror(+/+) mice (0.66+/-0.04, P<0.05). In addition, more extensive angiogenesis in Ror alpha(sg/sg) mice correlated with an increased expression of eNOS protein by 83+/-12% and 71+/-24% at 3 and 28 days, respectively (P<0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38+/-10% at day 28 (P<0.05). Conversely, no changes in VEGF expression were observed. Our study identifies for the first time a new role for Ror alpha as a potent negative regulator of ischemia-induced angiogenesis.

Animals↗
PubMed2001

Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction.

BACKGROUND: Shed membrane microparticles circulate in the peripheral blood of nonischemic (NI) patients and patients with myocardial infarction (MI). We investigated whether or not these microparticles would affect endothelium-dependent responses. METHODS AND RESULTS: Rat aortic rings with endothelium were exposed for 24 hours to circulating microparticles isolated from 7 patients with NI syndromes and 19 patients with acute MI. Endothelium-dependent relaxations to acetylcholine were not affected by high concentrations of microparticles from NI patients (P=0.80). However, significant impairment was observed in preparations exposed to microparticles from patients with MI at low and high concentrations, corresponding to 0.7-fold and 2-fold circulating plasma levels (P=0.05 and 0.001, respectively). Impairment was not affected by diclofenac (P=0.47), nor by the cell-permeable superoxide dismutase mimetic Mn(III)tetra(4-benzoic acid) porphyrin chloride (P=0.33), but it was abolished by endothelium removal or by N(omega)monomethyl-L-arginine. Relaxations to the calcium ionophore ionomycin were decreased in rings exposed to microparticles from MI patients (P=0.05 and 0.009 for low and high concentrations, respectively), but microparticles from NI patients had no effect (P=0.81). Finally, high concentrations of microparticles from MI patients affected neither endothelium-independent relaxation to sodium nitroprusside (P=0.59) nor expression of the endothelial nitric oxide synthase (P=0.43). CONCLUSIONS: Circulating microparticles from patients with MI selectively impair the endothelial nitric oxide transduction pathway and, therefore, could contribute to the general vasomotor dysfunction observed after MI, even in angiographically normal arteries.

Adult↗
PubMed2001

Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice.

Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of evidence supports a role for proinflammatory mediators in disease progression, the understanding of the role of the antiinflammatory component in the modulation of plaque progression is only at its beginning. TGF-beta1, -beta2, and -beta3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the direct role of TGF-beta in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-beta signaling using a neutralizing anti-TGF-beta1, -beta2, and -beta3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-beta signaling favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-beta in atherosclerosis.

Animals↗
PubMed2001

Vitamin C inhibits endothelial cell apoptosis in congestive heart failure.

BACKGROUND: Proinflammatory cytokines like tumor necrosis factor-alpha and oxidative stress induce apoptotic cell death in endothelial cells (ECs). Systemic inflammation and increased oxidative stress in congestive heart failure (CHF) coincide with enhanced EC apoptosis and the development of endothelial dysfunction. Therefore, we investigated the effects of antioxidative vitamin C therapy on EC apoptosis in CHF patients. METHODS AND RESULTS: Vitamin C dose dependently suppressed the induction of EC apoptosis by tumor necrosis factor-alpha and angiotensin II in vitro as assessed by DNA fragmentation, DAPI nuclear staining, and MTT viability assay. The antiapoptotic effect of vitamin C was associated with reduced cytochrome C release from mitochondria and the inhibition of caspase-9 activity. To assess EC protection by vitamin C in CHF patients, we prospectively randomized CHF patients in a double-blind trial to vitamin C treatment versus placebo. Vitamin C administration to CHF patients markedly reduced plasma levels of circulating apoptotic microparticles to 32+/-8% of baseline levels, whereas placebo had no effect (87+/-14%, P<0.005). In addition, vitamin C administration suppressed the proapoptotic activity on EC of the serum of CHF patients (P<0.001). CONCLUSIONS: Administration of vitamin C to CHF patients suppresses EC apoptosis in vivo, which might contribute to the established functional benefit of vitamin C supplementation on endothelial function.

Administration, Oral↗
PubMed2001

Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability.

BACKGROUND: Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown. METHODS AND RESULTS: In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01). CONCLUSIONS: These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.

Aged↗