Vincent Fontaine

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (18)51.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe-/- mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl2-induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta.
    International Journal of Molecular Medicine 05/2012; 30(2):288-94. · 1.96 Impact Factor
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    ABSTRACT: Mast cells (MCs) are inflammatory cells present in atherosclerotic lesions and neovascularized tissues. Recently, MCs were shown to modulate abdominal aortic aneurysm (AAA) formation in a mouse model. Progression of aneurysmatic disease process may also depend on intraluminal thrombus and neovascularization of the aneurysm wall. Here we investigated the relationship between MCs and inflammation, neovascularization, and the presence of intraluminal thrombus in human AAA. Specimens from AAAs and normal control aortas were analyzed with basic histology, immunohistochemical staining, and quantitative real-time polymerase chain reaction (PCR). Double immunostainings with endothelial cell markers CD31/CD34 and MC tryptase showed that, in contrast to histologically normal aorta, MCs in AAA were abundant in the media, but absent from the intima. Medial MCs and (CD31/CD34)(+) neovessels increased significantly in AAA compared with normal aorta (P < .0001 for both), and the highest densities of neovessels and MCs were observed in the media of thrombus-covered AAA samples. Also, the proportional thickness of aortic wall penetrated by the neovessels was significantly higher in the AAA samples (P < .0001), and the neovascularized area correlated with the density of medial MCs (P < .0001). In histologic analysis, the medial MCs were mainly located adjacent to the stem cell factor (SCF)(+) medial neovessels. Real-time PCR analysis also showed that mRNA levels of genes associated with neovascularization (vascular endothelial growth factor [VEGF], FLT1, VE-cadherin, CD31), and MCs (tryptase, chymase, cathepsin G) were higher in AAA samples than in controls. Demonstration of adhered platelets by CD42b staining and lack of endothelial cell (CD31/CD34) staining in the luminal surface of AAA specimens suggest endothelial erosion of the aneurysm walls. The results support participation of MCs in the pathogenesis of AAA, particularly regarding neovascularization of aortic wall.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 06/2009; 50(2):388-95; discussion 395-6. · 3.52 Impact Factor
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    ABSTRACT: Development and progression of acquired abdominal aortic aneurysms (AAAs) involve proteolytic activity. In the present study, we investigate the distribution of fibrinolytic system components within mural thrombi of human AAAs. 20 mural thrombi and the remaining AAA walls were dissected. The luminal, intermediate and abluminal thrombus layers, and media and adventitia were separately incubated in cell culture medium. Conditioned media were then analysed for plasminogen activators (PAs), plasminogen activator inhibitor-1 (PAI-1), free-plasmin, plasmin alpha(2)-antiplasmin complexes (PAPs) and D-dimers release. In parallel, PA and PAI-1 mRNA expression analysis was performed by RT-PCR. The study was completed by immunohistochemical localization of these components in AAA, ex vivo functional imaging using (99m)Tc-aprotinin as a ligand and measurement of PAP and D-dimer plasma levels. All fibrinolytic system components were present in each aneurysmal layer. However, the mural thrombus was the main source of active serine-protease release. Interestingly, the luminal layer of the thrombus released greater amounts of PAPs and D-dimers. This paralleled the preferential immunolocalization of plasminogen and PAs, and the (99m)Tc-aprotinin scintigraphic signal observed in the luminal pole of the thrombus. In contrast, mRNA expression analysis showed an exclusive synthesis of tPA and PAI-1 within the wall, whereas uPA mRNA was also expressed within the thrombus. Taken together, these results suggest that the increased plasma concentrations of PAPs and D-dimers found in AAA patients are related to mural thrombus proteolytic activity, thus explaining their known link with AAA progression. Components of the fibrinolytic system could also represent a target for functional imaging of thrombus activities in AAA.
    The Journal of Pathology 06/2007; 212(1):20-8. · 7.59 Impact Factor
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    ABSTRACT: The higher incidence of cerebral aneurysms (CAs) induced by enhanced arterial blood flow in Long Evans (LE) compared to Brown Norway (BN) rats suggests that intrinsic differences in high-flow arterial remodeling may be involved in determining CA susceptibility. Some aspects of this remodeling were compared in LE and BN rats after creation of an abdominal aortocaval fistula (ACF). At 4 days with ACF, aortic luminal cross-sectional area (LCSA) determined by morphometry was increased by 20% in LE but not in BN rats. mRNA levels, determined by RT-PCR, were higher in LE than in BN rats for collagen alpha1(I), collagen alpha1(III), MMP2 and its inhibitor TIMP1 at 19 days with ACF. Nitric oxide synthase (NOS) mRNA levels were higher in LE rats at 4 days for the inducible (NOS2) isoform and at 4 and 19 days for the neuronal (NOS1) isoform. Aortic LCSA and NOS1 mRNA levels were tightly correlated and NOS inhibition prevented ACF-induced aortic remodeling in the LE rat. MMP2 and MMP7 activity, evaluated by zymography at 4 days with ACF, did not greatly differ between BN and LE. These data suggest that a higher intrinsic ability for high-flow-induced arterial enlargement associated with NOS gene overexpression may be a possible genetic determinant in CA susceptibility.
    Journal of Vascular Research 02/2006; 43(3):217-28. · 2.43 Impact Factor
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    ABSTRACT: All forms of atheroma are characterized by a risk of arterial wall rupture leading to clinical complications. This involves medial and adventitial ruptures in abdominal aortic aneurysm (AAA) and intimal cap rupture in vulnerable atherothrombotic plaques. Extracellular proteases, including metalloproteinases, locally generated plasmin, and leukocyte elastase, are important molecular mediators of atheroma progression via their matrix degradation properties. The pathological evolution of AAA is linked to the biology of its associated mural thrombus. Indeed, in aneurysmal segments lined by a thrombus, the wall is thinner, the extracellular matrix more degraded, and the adventitial inflammatory response greater than in segments that are not. Several lines of evidence highlight the role of the thrombus, in AAA, as a reservoir of blood-borne proteases that conveys them from the lumen to the diseased wall. In stenosing atheroma, both previous and recent studies provide evidence that recurrent intraplaque hemorrhages play a dominant role in the evolution of the lesion toward vulnerability. In this review, we draw a parallel between the role of protease conveyance and activation of the mural thrombus in AAA and of intraplaque hemorrhages in stenosing atheroma. We hypothesize that intraplaque hemorrhages convey blood-borne proteases into lesions, where they are retained and activated upon thrombus/hematoma formation, thus contributing significantly to their deleterious action.
    Journal of the American College of Cardiology. 01/2006;
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    ABSTRACT: To explore possible mechanisms responsible for the absence of cell re-colonization of mural thrombi in aneurysms, we analyzed the release and storage of leukocyte proteases in the most luminal layer versus intermediate and abluminal layers of 10 mural thrombi of human abdominal aortic aneurysms. The luminal layer contained many polymorphonuclear leukocytes (PMNs), which released pro-matrix metalloproteinase (MMP)-9 and MMP-8. Leukocyte elastase was also stored and released by the luminal layer (immunohistochemistry, activity on synthetic substrates, and casein zymography). Acid buffer allowed extraction of leukocyte elastase from the luminal layer, which was inhibited by elastase inhibitors. Casein zymography of luminal extracts and conditioned medium from formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMNs exhibited a similar lysis pattern, corresponding to elastase activity. Smooth muscle cell (SMC) seeding resulted in colonization of the intermediate thrombus layer ex vivo but not of the luminal layer. Extracts of the luminal layer induced loss of anchorage of both cultured human smooth muscle cells and stromal cells of bone marrow origin (anoikis). This anoikis was prevented by preincubation of the extracts with serine protease inhibitors. Moreover, adhesion of human SMCs and stromal bone marrow cells on fibrin gels was strongly inhibited when the gel was preincubated with pure elastase, medium of fMLP-stimulated PMNs, or extracts of luminal layers of mural thrombi. This loss of cell anchorage was prevented by the preincubation of the medium or extracts with alpha(1)-antitrypsin, but not when alpha(1)-antitrypsin was added after binding of elastase to the fibrin gel. In conclusion, elastase released by PMNs trapped within the mural thrombus impairs the spontaneous anchorage of mesenchymal cells to a fibrin matrix. This phenomenon could be one mechanism by which cellular healing of the mural thrombus in aneurysms is prevented.
    American Journal Of Pathology 07/2004; 164(6):2077-87. · 4.60 Impact Factor
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    Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2004; 43(1):152-153.
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    ABSTRACT: The purpose of this study was to determine the pathogenic factors and molecular mechanisms involved in fibrosis of the atria. Fibrosis is an important component of the pathophysiology of atrial fibrillation, especially when the arrhythmia is associated with heart failure (HF) or atrial dilation. We used a rat model of myocardial infarction (MI) complicated by various degrees of left ventricular dysfunction and atrial dilation to study fibrosis and matrix metalloproteinase (MMP) activity in the left atrial (LA) myocardium by means of histologic, Western blot, zymographic, and immunohistologic techniques. Three months after surgical ligature of the left coronary artery, 27 rats had a large MI, 12 were in mild HF, and 15 in severe HF. Both groups had LA enlargement at the echocardiography. Masson's trichrome and picrosirius staining of tissue sections revealed marked fibrosis at the periphery of trabeculae and also surrounding myolytic myocytes, in both mild and severe HF. In mild HF, the activity and expression of the matrilysin MMP-7 were increased (122%), whereas in severe HF, both MMP-7 (211%) and the gelatinase MMP-2 (187%) were up-regulated. There were no changes in the expression or activity of MMP inhibitors, TIMP-1, -2, and -4. Immunostaining of cryosections showed that MMP-2 was present in the interstitial spaces, whereas MMP-7 accumulated in myolytic myocytes. Hemodynamic overload of the atria is an important pathogenic factor of fibrosis; MMP-7 appears to be involved in the early stage of this tissue remodeling process.
    Journal of the American College of Cardiology 08/2003; 42(2):336-44. · 14.09 Impact Factor
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    ABSTRACT: Acquired abdominal aortic aneurysms are usually associated with a mural thrombus through which blood continues to flow. Some early data suggest that aneurysmal evolution correlates with the biological activity of the thrombus. Our hypothesis was therefore that the thrombus could adsorb blood components and store, release, and participate in the activation of proteases involved in aneurysmal evolution. For this purpose, we have explored both the metalloproteinase and fibrinolytic systems in the thrombus and the wall of human aneurysms. We have first investigated blood clot formation and lysis in vitro. Spontaneous clotting induces a release of promatrix metalloproteinase (pro-MMP)-9 into the serum that was fourfold higher than in paired control plasma (P < 0.001). Fibrinolysis progressively released more MMP-9 in a time-dependent manner (P < 0.01). After selective isolation, we demonstrated that polymorphonuclear leukocytes are the main source of MMP-9 release during clot formation. Protease content was then analyzed in 35 mural thrombi and walls of human abdominal aortic aneurysms sampled during surgical repair. In 15 aneurysms, the liquid phase at the interface between the thrombus and the wall was sampled separately. Both thrombus and wall contained MMP-2 and MMP-9 but the ratio MMP-9/MMP-2 was higher in the thrombus than in the wall. The liquid interface also contained active MMP-9. Immunohistochemistry of the thrombus confirmed these findings, showing the presence of polymorphonuclear leukocytes at the luminal pole of the thrombus, co-localizing with MMP-9 storage. In contrast, MMP-3 and MMP-7 were only present in the aneurysmal wall. Plasminogen was present in the mural thrombus but plasmin activity was present in both thrombus and wall. In the liquid interface, plasmin-alpha(2)-anti-plasmin complexes were detected demonstrating in vivo the activation of plasminogen. In contrast, u-PA and t-PA were detectable only in the wall, suggesting that plasminogen present in the thrombus could be activated by factors secreted by the arterial wall. This was demonstrated in vitro, in which co-incubation of thrombus and wall extracts generated plasmin in the presence of a fibrin matrix and activated MMPs. In conclusion, our study strongly suggests that the mural thrombus, by trapping polymorphonuclear leukocytes and adsorbing plasma components could act as a source of proteases in aneurysms that may play a critical role in enlargement and rupture.
    American Journal Of Pathology 12/2002; 161(5):1701-10. · 4.60 Impact Factor
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    ABSTRACT: Aneurysm is an arterial dilatation with risk of rupture. It is a disease of the media characterized by the destruction of extracellular matrix proteins (especially elastin) involving different proteases: matrix metalloproteinases, fibrinolytic proteases (plasminogen activators, plasmin), leucocyte elastase, and by the absence of scarring process. There is an imbalance in the aortic wall between proteolytic and antiproteolytic activities, the former being overexpressed (by inflammatory cells infiltrating the aortic wall on the adventitial side, and the endoluminal thrombus), the latter (normally synthesized and secreted by vascular smooth muscle cells) being decreased in relation to the disappearance of smooth muscle cells.
    La Revue du praticien 06/2002; 52(10):1061-5.
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    ABSTRACT: The rat model of chronic intoxication by N(G) -nitro-L-arginine methyl ester (L-NAME) induces severe systemic arterial hypertension and progressive ischemic lesions in the central nervous system and kidneys. We investigated the possible molecular basis of these thrombotic events. Administration of L-NAME increased plasma markers of thrombin generation, thrombin-antithrombin complexes, and soluble glycoprotein V, measured by specific ELISA. Thrombin generation in vivo was associated with ex vivo platelet desensitization to adenosine 5'-diphosphate and collagen-induced aggregation. In the aortic layers and renal arterioles, tissue factor mRNA (semi-quantitative RT-PCR) and activity (coagulation assay) were increased. In contrast, tissue factor activity was not modified in glomeruli. In parallel, an impairment of the fibrinolytic system was demonstrated by an increase in plasma levels and arterial secretion of plasminogen activator inhibitor-1. In the arterial wall, plasminogen activator inhibtor-1 mRNA was significantly increased. Moreover, antifibrinolytic activity, studied by fibrin reverse zymography, was increased whereas all tissue-plasminogen activator activity secreted by the hypertensive arterial wall was detected as complexes with its specific inhibitor. In animals treated with the angiotensin-converting enzyme (ACE) inhibitor Zofenil, all of these parameters remained at control levels. These results indicate that chronic blockade of nitric oxide production in rats results in enhancement of blood markers of thrombin generation associated with tissue factor induction and impairment of fibrinolysis in the vascular wall, which may contribute to the thrombotic complications associated with hypertension.
    Molecular Medicine 05/2002; 8(4):169-78. · 4.47 Impact Factor
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    ABSTRACT: The extracellular matrix provides a structural framework essential for the functional properties of vessel walls. The three dimensional organization of the extracellular matrix molecules--elastin, collagens, proteoglycans and structural glycoproteins--synthesized during fetal development--is optimal for these functions. Early in life, the vessel wall is subjected to injury: lipid deposition, hypoxia, enzyme secretion and reactive oxygen species production during inflammatory processes, and the extracellular matrix molecules are hydrolyzed by proteases--matrix metalloproteinases, leukocyte elastase, etc. In uninjured arteries and veins, some proteases are constitutively expressed, but through the control of their activation and/or their inhibition by inhibitors, these proteases have a very low activity. During the occurrence of vascular pathologies--atherosclerosis, hypertension, varicosis, restenosis, etc.--the balance between proteases and their inhibitors is temporally destroyed through the induction of matrix metalloproteinase gene expression or the secretion of enzymes by inflammatory cells. Smooth muscle cells, the most numerous cells in vascular walls, have a high ability to respond to injury through their ability to synthesize extracellular matrix molecules and protease inhibitors. However, the three dimensional organization of the newly synthesized extracellular matrix is never functionally optimal. In some other pathologies--aneurysm--the injury overcomes the responsive capacity of smooth muscle cells and the quantity of extracellular matrix decreases. In conclusion, care should be taken to maintain the vascular extracellular matrix reserve and any therapeutic manipulation of the protease/inhibitor balance must be perfectly controlled, because an accumulation of abnormal extracellular matrix may have unforeseen adverse effects.
    Pathologie Biologie 06/2001; 49(4):326-32. · 1.67 Impact Factor
  • Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2001; 33(6).
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    ABSTRACT: It has previously been reported that hypertension induced by the chronic blockade of NO production is characterized by a proinflammatory phenotype of the arterial wall associated with a periarterial accumulation of inflammatory cells. In the present study, the cellular and molecular mechanisms involved in the luminal and perivascular accumulation of inflammatory cells were evaluated in the aortas of NG-nitro-L-arginine methyl ester (L-NAME)-treated rats. Because the medial layer remains intact, putative markers of the resistance of the vascular wall to cell migration and to oxidative stress were also explored. For this purpose, monocyte adhesion, cytokine expression, superoxide anion production, and nuclear factor-kB (NF-kB) activation were assessed in the aortas of L-NAME-treated rats. Expressions of tissue inhibitor of metalloproteinases-1 (TIMP-1) and heme oxygenase-1 (HO-1) in the aortic wall were also studied as possible markers of such resistance. Chronic blockade of NO production increased ex vivo monocyte adhesion to the endothelium, increased the production of superoxide anions, and activated the NF-kB system. In concert with this modification of the redox state of the vascular wall in L-NAME-treated rats, the expression of proinflammatory cytokines interleukin-6, monocyte chemoattractant protein-1, and macrophage colony-stimulating factor was increased. In parallel, expressions of both TIMP-1 and HO-1 were increased. All these changes were prevented by treatment with an angiotensin-converting enzyme inhibitor (Zofenopril). Hypertension associated with a proinflammatory phenotype of the vascular wall induced by blockade of NO production could be due to an increase in oxidative stress, which, in turn, activates the NF-kB system and increases gene expression. In parallel, the arterial wall overexpresses factors such as TIMP-1 and HO-1, which could participate in the resistance to cell migration and oxidative stress. (Hypertension. 2000;36:103-109.)
    Hypertension 08/2000; 36(1). · 6.87 Impact Factor
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    ABSTRACT: Aneurysm is an arterial dilatation with risk of rupture. Contrary to atherosclerosis - which predominantly involves the intima layer - aneurysm is a disease of the media. It is characterized by destruction of extracellular matrix proteins (especially elastin) induced by different proteases: matrix metalloproteinases (some of them display elastolytic activity), and fibrinolytic serine-proteases (plasminogen activators plasmin), the latter indirectly taking part in elastolysis through matrix metalloproteinases activation. There is an imbalance in the aortic wall beteen proteolytic and antiproteolytic enzymatic activities, the former being overexpressed (by inflammatory mononuclear cells infiltrating the aortic wall, and in endoluminal thrombus), the latter (normally synthesized and secreted by vascular smooth muscle cells) being decreased. Another characteristic of aneurysm development is the disappearance of smooth muscle cells, which could be due to proteinase-induced pericellular proteolysis and cell detachmentreduced apoptosis. Studies (in vitro, in vivo, and usinq experimental aneurysm models) describing this imbalance between aortic wall proteolytic and antiproteolytic activities have identified potential candidate-genes of susceptibility, plasma markers of evolutivity, and therapeutic targets.
    13(6):348-354.
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    ABSTRACT: BACKGROUND: The rat model of chronic intoxication by N(G) -nitro-L-arginine methyl ester (L-NAME) induces severe systemic arterial hypertension and progressive ischemic lesions in the central nervous system and kidneys. We investigated the possible molecular basis of these thrombotic events. METHODS AND RESULTS: Administration of L-NAME increased plasma markers of thrombin generation, thrombin-antithrombin complexes, and soluble glycoprotein V, measured by specific ELISA. Thrombin generation in vivo was associated with ex vivo platelet desensitization to adenosine 5'-diphosphate and collagen-induced aggregation. In the aortic layers and renal arterioles, tissue factor mRNA (semi-quantitative RT-PCR) and activity (coagulation assay) were increased. In contrast, tissue factor activity was not modified in glomeruli. In parallel, an impairment of the fibrinolytic system was demonstrated by an increase in plasma levels and arterial secretion of plasminogen activator inhibitor-1. In the arterial wall, plasminogen activator inhibtor-1 mRNA was significantly increased. Moreover, antifibrinolytic activity, studied by fibrin reverse zymography, was increased whereas all tissue-plasminogen activator activity secreted by the hypertensive arterial wall was detected as complexes with its specific inhibitor. In animals treated with the angiotensin-converting enzyme (ACE) inhibitor Zofenil, all of these parameters remained at control levels. CONCLUSIONS: These results indicate that chronic blockade of nitric oxide production in rats results in enhancement of blood markers of thrombin generation associated with tissue factor induction and impairment of fibrinolysis in the vascular wall, which may contribute to the thrombotic complications associated with hypertension.
    Mol Med. 8(4):169-78.
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    ABSTRACT: Background: The rat model of chronic intoxication by NG-nitro-L-arginine methyl ester (L-NAME) induces severe systemic arterial hypertension and progressive ischemic lesions in the central nervous system and kidneys. We investigated the possible molecular basis of these thrombotic events. Methods and Results: Administration of L-NAME increased plasma markers of thrombin generation, thrombin-antithrombin complexes, and soluble glycoprotein V, measured by specific ELISA. Thrombin generation in vivo was associated with ex vivo platelet desensitization to adenosine 5?-diphosphate and collagen-induced aggregation. In the aortic layers and renal arterioles, tissue factor mRNA (semi-quantitative RT-PCR) and activity (coagulation assay) were increased. In contrast, tissue factor activity was not modified in glomeruli. In parallel, an impairment of the fibrinolytic system was demonstrated by an increase in plasma levels and arterial secretion of plasminogen activator inhibitor-1. In the arterial wall, plasminogen activator inhibtor-1 mRNA was significantly increased. Moreover, antifibrinolytic activity, studied by fibrin reverse zymography, was increased whereas all tissue-plasminogen activator activity secreted by the hypertensive arterial wall was detected as complexes with its specific inhibitor. In animals treated with the angiotensin-converting enzyme (ACE) inhibitor Zofenil, all of these parameters remained at control levels. Conclusions: These results indicate that chronic blockade of nitric oxide production in rats results in enhancement of blood markers of thrombin generation associated with tissue factor induction and impairment of fibrinolysis in the vascular wall, which may contribute to the thrombotic complications associated with hypertension.
    8(4):169-178.
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    ABSTRACT: Aneurysm is an arterial dilatation with risk of rupture. It is a disease of the media characterized by the destruction of extracellular matrix proteins (especially elastin) involving different proteases: matrix metalloproteinases, fibrinolytic proteases (plasminogen activators, plasmin), leucocyte elastase, and by the absence of scarring process. There is an imbalance in the aortic wall between proteolytic and antiproteolytic activities, the former being overexpressed (by inflammatory cells infiltrating the aortic wall on the adventitial side, and the endoluminal thrombus), the latter (normally synthesized and secreted by vascular smooth muscle cells) being decreased in relation to the disappearance of smooth muscle cells.
    52(10):1061-1065.

Publication Stats

543 Citations
51.80 Total Impact Points

Institutions

  • 2009
    • Karolinska Institutet
      • Center for Molecular Medicine - CMM
      Solna, Stockholm, Sweden
  • 2001–2006
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2002
    • Unité Inserm U1077
      Caen, Lower Normandy, France