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Biomedical subjects

Alain Tedgui

Publications and source records attributed to Alain Tedgui.

50 records · Page 3Linked to original sources
PubMed2003

Cellular mechanics and gene expression in blood vessels.

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. Alterations in stretch or shear stress invariably produce transformations in the vessel wall that will aim to accommodate the new conditions and to ultimately restore basal levels of tensile stress and shear stress. 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. Beyond the structural modifications incurred, mechanical forces can also initiate complex signal transduction cascades leading to functional changes within the cell. Many intracellular pathways, including the MAP kinase cascade, are activated by flow or stretch and initiate, via sequential phosphorylations, the activation of transcription factors and subsequent gene expression.

Animals↗
PubMed2002

Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice.

Several clinical and angiographic intervention trials have shown that fibrate treatment leads to a reduction of the coronary events associated to atherosclerosis. Fibrates are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha) that modulate risk factors related to atherosclerosis by acting at both systemic and vascular levels. Here, we investigated the effect of treatment with the PPARalpha agonist fenofibrate (FF) on the development of atherosclerotic lesions in apolipoprotein (apo) E-deficient mice and human apoA-I transgenic apoE-deficient (hapoA-I Tg x apoE-deficient) mice fed a Western diet. In apoE-deficient mice, plasma lipid levels were increased by FF treatment with no alteration in the cholesterol distribution profile. FF treatment did not reduce atherosclerotic lesion surface area in the aortic sinus of 5-month-old apoE-deficient mice. By contrast, FF treatment decreased total cholesterol and esterified cholesterol contents in descending aortas of these mice, an effect that was more pronounced in older mice exhibiting more advanced lesions. Furthermore, FF treatment reduced MCP-1 mRNA levels in the descending aortas of apoE-deficient mice, whereas ABCA-1 expression levels were maintained despite a significant reduction of aortic cholesterol content. In apoE-deficient mice expressing a human apoA-I transgene, FF increased human apoA-I plasma and hepatic mRNA levels without affecting plasma lipid levels. This increase in human apoA-I expression was accompanied by a significant reduction in the lesion surface area in the aortic sinus. These data indicate that the PPARalpha agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis.

Animals↗
PubMed2002

Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb.

Identification of factors that may stimulate ischemia-induced neovascularization without increasing atherosclerotic plaque progression is of major therapeutic importance. We hypothesized that interleukin-18 binding protein (IL-18BP), a major antiinflammatory protein with plaque-stabilizing activities, may affect the neovascularization in mice ischemic hindlimb. Ischemia was produced by artery femoral occlusion in mice that were subjected to in vivo intramuscular electrotransfer of either an empty plasmid or a murine IL-18BP plasmid. Angiographic score, capillary density (CD31 staining), and laser Doppler perfusion data at day 28 showed significant improvement in ischemic/nonischemic leg ratio by respectively 1.6-, 1.4-, and 1.5-fold in IL-18BP-treated mice compared with controls (P<0.01). This was associated with a significant 2-fold increase in both vascular endothelial growth factor (VEGF) and phospho-Akt protein content in the ischemic hindlimb of IL-18BP-treated mice (P<0.05). Similar results were obtained in IL-18-deficient mice. Because bone marrow-derived endothelial progenitor cells (BM-EPCs) are involved in postnatal vasculogenesis, EPCs were isolated and cultivated from bone marrow mononuclear cells. IL-18BP treatment led to a significant 1.8-fold increase in the percentage of BM-EPCs characterized as cells positive for both AcLDL-Dil and von Willebrand factor (P<0.001). In conclusion, IL-18BP stimulates ischemia-induced neovascularization in association with an activation of VEGF/Akt signaling and an increase in BM-EPCs mobilization and differentiation. Our findings strongly suggest a major antiangiogenic role of endogenous IL-18 in postischemic injury.

Angiography↗
PubMed2002

Time courses of apoptosis and cell proliferation and their relationship to arterial remodeling and restenosis after angioplasty in an atherosclerotic rabbit model.

OBJECTIVES: We sought to evaluate whether cellular mass changes (including apoptosis and proliferation) after arterial injury could interact with restenosis and arterial remodeling. BACKGROUND: The mechanisms controlling arterial remodeling after angioplasty remain poorly understood. Apoptosis and cell proliferation have been previously described after balloon angioplasty. However, their importance in the occurrence of arterial remodeling and restenosis is unknown. METHODS: Atherosclerosis was induced in 48 femoral arteries of New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed in 40 arteries. Apoptosis, cell proliferation, residual stenosis and arterial remodeling were evaluated at 2 h and 3, 7, 14, 21 and 28 days after angioplasty. RESULTS: Cell proliferation and apoptosis profiles were similar, but the peak in cell proliferation occurred approximately four days earlier than the peak in apoptosis in the neointima and media. Apoptosis density was positively correlated with arterial remodeling in the neointima and media (r = 0.69, p = 0.005 and r = 0.50, p = 0.05, respectively). Moreover, residual stenosis was inversely correlated with apoptosis density in the neointima and media (r = -0.62, p = 0.008 and r = -0.52, p = 0.04, respectively). In contrast, cell proliferation was independent of restenosis and arterial remodeling. CONCLUSIONS: In this model, cell proliferation preceded apoptosis throughout the four weeks after angioplasty. Apoptosis was inversely correlated with restenosis. Interestingly, apoptosis was also related to enlargement remodeling after balloon angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed2002

Smooth muscle dysfunction in resistance arteries of the staggerer mouse, a mutant of the nuclear receptor RORalpha.

Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily. The mouse mutant staggerer (sg/sg) carries a deletion within the RORalpha gene. RORalpha plays a major role in cellular differentiation during development and growth. In the present study, we found a lower mean arterial blood pressure in sg/sg than in +/+ mice (80.1+/-1.2 and 87.0+/-0.9 mm Hg, respectively; P<0.0002) and a smaller increase in blood pressure after in vivo injections of phenylephrine. To elucidate the mechanisms responsible for this phenotype, we investigated the vascular reactivity of large vessels (aorta and carotid arteries) and small resistance mesenteric arteries in response to mechanical forces or vasoactive agents. Arteries from sg/sg and +/+ mice were studied in vitro in arteriographs. Vascular responses of large vessels to all stimuli were similar in both groups. However, we found a markedly altered vascular function in mesenteric arteries from sg/sg mice. Flow-induced dilation, pressure-induced myogenic tone, responses to endothelium-dependent or -independent vasodilators, and responses to vasoconstrictors were significantly reduced in sg/sg compared with +/+ mice. We also determined by Western blot analysis the expression of smooth muscle (SM)-myosin, calponin, and heavy (h)-caldesmon, in large and small arteries of sg/sg and +/+ mice, and found a marked decrease in the expression of these contractile proteins in mesenteric arteries of sg/sg mice. Our findings provide the first evidence that functional RORalpha is required for normal contractile phenotype of smooth muscle cells (SMCs) in small resistance arteries and suggest that RORalpha might be involved in the differentiation of SMCs in mesenteric arteries.

Animals↗
PubMed2002

Expression and regulation of the nuclear receptor RORalpha in human vascular cells.

Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily. Using RT-PCR, RORalpha mRNA was identified in human aortic smooth muscle cells (hASMC), endothelial cells (EC), as well as in human mammary arteries and atherosclerotic plaques. We found a predominant expression of RORalpha1 in hASMC, and RORalpha4 in EC. RORalpha2 and RORalpha3 were not detected. In arteries, RORalpha4 was predominant compared with RORalpha1. In atherosclerotic plaques, RORalpha expression was significantly decreased. In hASMC stimulated with cytokines, RORalpha expression was increased by 2.5-fold. RORalpha mRNA was also significantly increased (approximately 2-fold) in hASMC and EC cultured under hypoxia.

Aorta↗
PubMed2002

Age-related phenotypes in the staggerer mouse expand the RORalpha nuclear receptor's role beyond the cerebellum.

The homozygous mutant mouse staggerer (RORa(sg)/RORa(sg)), was initially described as ataxic, due to the presence of massive neurodegeneration in the cerebellum [Science 136 (1962) 610]. The identification of the widely expressed Retinoic acid receptor-related Orphan Receptor, NR1F1 (RORalpha) gene as the site of mutation in the staggerer mouse has led to great progress in understanding the molecular basis of its phenotype in recent years [Nature 379 (1996) 736]. RORalpha is a transcription factor, belonging to the nuclear receptor superfamily, for which no natural ligand has yet been identified. Mice engineered for the disruption of the gene encoding RORalpha display the same cerebellar atrophic phenotype as the staggerer mouse [Proc. Natl. Acad. Sci. USA 95 (1998) 3960]. More recently, it has been shown that the mutation is semi-dominant, as heterozygous animals display an increased loss of Purkinje cells with age. Furthermore, a number of additional phenotypes outside the nervous system have recently been identified. These include a greater susceptibility to atherosclerosis [Circulation 15 (1998) 2738], immunodeficiencies linked to the overexpression of inflammatory cytokines [J. Neurochem. 58 (1992) 192], abnormalities in the formation and maintenance of bone tissue [Proc. Natl. Acad. Sci. USA 97 (2000) 9197] and changes in muscle differentiation [Nucleic Acids Res. 27 (1999) 411]. Thus, RORalpha has been directly linked to a number of age-related pathologies of great medical interest.

Age Factors↗
PubMed2002

Decreased arteriolar density in endothelial nitric oxide synthase knockout mice is due to hypertension, not to the constitutive defect in endothelial nitric oxide synthase enzyme.

BACKGROUND: Hypertension in endothelial nitric oxide synthase knockout (eNOS-/-) mice is believed to be partly due to altered vasodilatation. However, nitric oxide (NO) is also known to play an important part in angiogenesis. OBJECTIVE: To investigate whether capillary and arteriolar density were impaired in eNOS-/- mice, as this could account for increased vascular resistance and hypertension. METHODS: Using immunohistochemistry with mouse monoclonal smooth muscle alpha-actin antibody to detect arterioles and rabbit polyclonal fibronectin antibody to detect capillaries, we quantified arteriolar and capillary density in the left ventricle and in the gracilis muscle from eNOS-/- mice compared with those in C57BL6J littermates (n = 6-8) in 8- and in 12-week-old mice. In a second set of experiments, we treated 8-week-old normotensive eNOS-/- mice with the antihypertensive vasodilator, hydralazine, for 1 month. RESULTS: Eight-week-old eNOS-/- mice were normotensive and presented similar arteriolar and capillary densities in cardiac and skeletal muscles compared with those in eNOS+/+ mice. Twelve-week-old eNOS/- mice were hypertensive (mean arterial pressure 118 +/- 21 mmHg compared with 64 +/- 2 mmHg; P < 0.05). Capillary densities were similar in eNOS-/- mice and eNOS+/+ mice in the heart (4154 +/- 123 and 4051 +/- 247/mm2, respectively) and in skeletal muscle (961 +/- 40 and 1025 +/- 41/mm2, respectively). Arteriolar densities were 15% lower in skeletal muscle and in the heart in eNOS-/- mice than in the eNOS+/+ control group (P < 0.05). Hydralazine prevented hypertension and arteriolar rarefaction in eNOS-/- mice, whereas capillary density was unaffected by treatment with the vasodilator. CONCLUSION: In young non-hypertensive eNOS-/- mice, the lack of eNOS did not affect microvascular densities in either of the muscles studied. In adult hypertensive eNOS-/- mice, we observed a lower arteriolar density, but a similar capillary density compared with controls. Hydralazine prevented hypertension and arteriolar rarefaction in adult mice, suggesting a non-NO-dependent pathway. Capillary density was not affected by hydralazine.

Animals↗
PubMed2002

The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives.

PURPOSE OF REVIEW: Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Transforming growth factors beta 1, 2 and 3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system, and have been suggested to play a role in the pathogenesis of atherosclerosis. RECENT FINDINGS: In the present review, we discuss recent developments in the role of transforming growth factor beta in the regulation of the immuno-inflammatory balance that modulates atherosclerosis. Such studies strongly suggest that the inhibition of endogenous transforming growth factor beta signalling favours the development of atherosclerotic lesions with an increased inflammatory component (T cells and macrophages) and decreased collagen content, features that are characteristic of unstable atherosclerotic plaques. SUMMARY: Transforming growth factor beta is identified as a critical modulator of the immuno-inflammatory balance in atherosclerosis, and a crucial plaque-stabilizing factor. Future studies should aim at defining the precise molecular mechanisms responsible for this protective effect, and developing immunomodulatory strategies based on the promotion of transforming growth factor beta activity (T regulatory T helper type 3 cells) to limit disease complications.

Animals↗
PubMed2002

Mechanisms of blood flow-induced vascular enlargement.

Chronic changes in wall shear stress lead to vascular remodeling, characterized by increased vascular wall diameter and thickness, to restore wall shear stress values to baseline. Release of nitric oxide from endothelial cells exposed to excessive shear is a fundamental step in the remodeling process, and potentially triggers a cascade of events, including growth factor induction and matrix metalloproteinase activation, that together contribute to restructuralization of the vessel wall. Understanding these processes could help explain how changes in blood vessel wall structure occur in the context of atherosclerosis or aortic aneurisms.

Animals↗
PubMedDate not supplied

Age and gender effects on apoptosis in the human coronary arterial wall.

The relationship between aging and apoptosis remains unclear. We wondered whether apoptosis could be enhanced in arterial aging in the absence of overt or advanced arterial disease. Apoptosis-related proteins were investigated using three methods: TdT-mediated dUTP digoxigenin nick end labeling (TUNEL) technique, active cysteine-dependant aspartate specific proteases (caspase)-3 and poly ADP-ribose polymerase (PARP) in coronary arteries of human subjects ranging from 25 to 92 years. We found no significant correlation between age and the apoptotic index using the three methods. The percentage of active caspase-3 positive cells was found to be significantly higher in men than in women (9.11 +/- 12.3 cells/mm(2) versus 2.01 +/- 4.55 cells/mm(2), respectively, p = 0.017). These sex-related differences did not reach statistical significance using TUNEL (9.93 +/- 17 and 2.61 +/- 4.58 cells/mm(2), p = 0.32) and PARP methods (3.42 +/- 7.74 and 0.86 +/- 0.95 cells/mm(2), p < 0.49). This is the first report of detection of apoptotic cells in the human arterial wall in adult subjects free from arterial diseases. Apoptosis is an attractive hypothesis to account for organ aging, but our study suggests that apoptosis is not a key factor in aging of the arterial wall.

Adult↗
PubMedDate not supplied

Chemokine receptor CCR1 disruption in bone marrow cells enhances atherosclerotic lesion development and inflammation in mice.

Several chemokines or chemokine receptors are involved in atherogenesis. CCR1 is expressed by macrophages and lymphocytes, two major cell types involved in the progression of atherosclerosis, and binds to lesion-expressed ligands. We examined the direct role of the blood-borne chemokine receptor CCR1 in atherosclerosis by transplanting bone marrow cells from either CCR1+/+ or CCR1-/- mice into low-density lipoprotein-receptor (LDLr)-deficient mice. After exposure to an atherogenic diet for 8 weeks, no differences in fatty streak size or composition were detected between the 2 groups. After 12 weeks of atherogenic diet, however, an unexpected 70% increase in atherosclerotic lesion size in the thoracic aorta was detected in the CCR1-/- mice, accompanied by a 37% increase in the aortic sinus lesion area. CCR1-/- mice showed enhanced basal and concanavalin A-stimulated IFN-gamma production by spleen T cells and enhanced plaque inflammation. In conclusion, blood-borne CCR1 alters the immuno-inflammatory response in atherosclerosis and prevents excessive plaque growth and inflammation.

Animals↗