Elevated plasminogen activator inhibitor (PAI-1) activity levels, hyperlipemia, hypertension, impaired glucose tolerance and obesity, in particular central obesity, are all related to increased risk for the development of cardiovascular disease.Some risk factors are known to be and shown to be influenced by dietary habits. One aim of this study was to determine the distribution of PAI-1 activity and its linkage to serum lipids, body build, glucose and insulin (including glucose tolerance) among healthy men and women. Another aim was to elucidate the effects of different diet programes on the relationship between PAI-1 activity, serum lipid, glucose and insulin levels. Two cross-sectional studies, involving 260 individuals, the Norsjö study 1986, the mean PAI-1 activity among 30-60 year-old men was 7.9 U/mL and among women 7.8 U/mL. Both men and women with a body mass index over 27 kg/m2 had higher PAI-1 activity, tPA antigen, fasting insulin and insulin responses following an oral glucose tolerance test than persons with body mass index &lt;27. They also had lower HDL-cholesterol. Women with a high waist/hip circumference ratio had a higher mean PAI-1 activity, tPA antigen, triglyceride, blood pressure and insulin response to an oral glucose tolerance test than women with low or normal waist/hip ratio. Men with high waist/hip ratio had higher tPA antigen, glucose and insulin responses to an oral glucose tolerance test than men with low or normal waist/hip ratio. In two dietary studies different low-energy diets (a juice fast or a weight reduction program) were followed. PAI-1 activity was decreased in both cases. In a third dietary study, transition from a high-fat/low-carbohydrate diet to a low-fat/high-carbohydrate diet decreased PAI-1 activity provided that it did not also cause a substantial increase in triglycerides or glucose. In a fourth dietary study the regular diet was supplemented with oat-husk. PAI-1 activity was reduced; a small increase in glucose but not in triglyceride levels was observed. On the basis of these results it is concluded that PAI-1 activity levels are associated with constitutional factors such as body mass index and waist/hip ratio. PAI-1 is elevated in obesity. Nutritional factors are also of importance for the PAI-1 activity levels. PAI-1 activity levels can be reduced by dietary regiments such as low-energy diets or high-fiber diets. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 6 uppsatser.</p> / digitalisering@umu

Motivation: Hypertension is a fast growing health risk, leading to increased incidences of cardiovascular dysfunction and mortality. However, the prevalence of hypertension is higher in some ethnic populations than others. Several South African studies have found that the African population is more susceptible to the development of hypertension, compared to the Caucasian population. Cardiovascular dysfunction is often accompanied by elevated levels of uric acid (UA) and plasminogen activator inhibitor-I (PAI-1) and both are factors associated with the metabolic syndrome. A lack of data regarding the association of UA and PAL1 with cardiovascular dysfunction in a South African context, serves as a motivation for conducting this study. Objective: To determine the association of UA and PAI-1 with cardiovascular dysfunction in African and Caucasian women from South Africa. Methodology: The manuscript presented in Chapter 2 made use of the data obtained in the POWIRS (Profiles of Obese Women with the Insulin Resistance Syndrome) study. A group of 102 African women and 115 Caucasian women, living in the North West Province of South Africa, were recruited according to their body mass indexes. The groups were divided into lean, overweight and obese according to their body mass index. Anthropometric and cardiovascular measurements were taken and determinations were done of their blood lipid profiles, UA. PAI-1, fasting insulin and glucose levels, HOMA-IR (homeostasis model assessment-insulin resistance) and leptin levels. The subject's total dietary protein intake was determined by means of a dietary questionnaire. Comparisons between the groups were done using an independent t-test as well as a multiple analysis of covariance (MANCOVA) whilst adjusting for certain variables. Each ethnic group was divided into UA and PAI-1 tertiles, for comparison between the 1" and 3' tertiles. Correlation ~0efIi~ientS were determined to show any associations between UA and PAI-1 with cardiovascular variables as well as variables associated with the metabolic syndrome. Forward stepwise multiple regression analyses were performed using UA and PAL1 respectively as dependent variables. The study was approved by the Ethics committee of the North-West University and all the subjects gave informed consent in writing. The reader is referred to the experimental procedure section in Chapter 2 for a more detailed description of the subjects, study design and analytical procedures used in this dissertation. Results and conclusion: Results from the POWIRS-study showed that despite the African women's higher blood pressure, they had significantly lower levels of UA and PAI-I compared to the Caucasian women. Although the Caucasian women had significantly higher circulating levels of UA and PAI-1, they showed no sign of cardiovascular dysfunction. The detrimental effects might, however, become more noticeable with an increase in age. From this study it is concluded that UA and PAL1 is not associated with the increased blood pressure in young African women. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2006.

Motivation Soluble urokinase plasminogen activator receptor (suPAR) is a known inflammatory marker, which is found in various body fluids. SuPAR reflects the immune and pro–inflammatory status of patients caused by HIV and tuberculosis, amongst others. However, recent studies have shown that suPAR is related to cardiovascular function. The cardiovascular health of the black South African population is a major health concern as this group suffers mostly from hypertension and stroke, leading to an alarming increase in cardiovascular morbidity and mortality. SuPAR may be able to contribute to early detection and prevention of cardiovascular diseases. No studies regarding the associations of suPAR with cardiovascular function have been investigated on black South Africans. Objectives To investigate suPAR as a possible marker of cardiovascular function in African and Caucasian men and women, by determining possible gender and ethnic–specific associations of suPAR with cardiovascular function. Methodology There were 207 African and 314 Caucasian men and women (aged 20–79 yrs.) included in this study. High–sensitivity C–reactive protein, glucose, lipids and creatinine were determined in fasting serum and suPAR was analyzed in plasma samples. Blood pressure was measured using the OMRON apparatus (HEM–747), with a 5–min rest interval between measurements. The Finometer device was used to determine the Windkessel compliance and the carotid dorsalis–pedis pulse wave velocity (PWV) was measured with the Complior (SP acquisition system) on the left side of each subject in the supine position. The means, adjusted means and proportions were compared between the groups by using independent t–tests, analysis of co–variance and the chi–square test, respectively. Associations were investigated between cardiovascular variables and suPAR using single and multiple regression analyses with either pulse wave velocity, systolic blood pressure, diastolic blood pressure or Windkessel compliance as dependent variable. Covariates included were age, body mass index, smoking, alcohol use, physical activity, glucose and high–density lipoprotein cholesterol. Results and conclusion SuPAR levels were significantly higher in Africans (P<0.001) compared to Caucasians. After adjusting for body mass index, suPAR increased significantly with age in all groups, except for African women. Moreover, the suPAR levels of African men and women were significantly higher than the Caucasians within each age quartile. While adjusting for age and body mass index, the cardiovascular profiles of the African and Caucasian men were less favourable compared to women, but suPAR levels were significantly higher in Caucasian women compared to men. In single regression, various measures of cardiovascular function correlated with suPAR in African men and Caucasian men and women. After adjusting for confounders the associations disappeared in Caucasian women, and remained nonsignificant in the African women. However, the association between PWV and suPAR remained significant in African men (B=0.19; P=0.030), while the association of systolic blood pressure (B=0.20; P=0.017), diastolic blood pressure (B=0.17; P=0.020) and Windkessel compliance (B=–0.14; P=0.004) with suPAR remained significant in Caucasian men. In conclusion, Africans presented higher suPAR levels compared to Caucasians, even when stratified by age. Gender specific associations indicated that suPAR was associated with arterial stiffness in African and Caucasian men only, therefore, indicating that suPAR could be a possible biomarker for predicting cardiovascular dysfunction. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2011.

Motivation Soluble urokinase plasminogen activator receptor (suPAR) is a known inflammatory marker, which is found in various body fluids. SuPAR reflects the immune and pro–inflammatory status of patients caused by HIV and tuberculosis, amongst others. However, recent studies have shown that suPAR is related to cardiovascular function. The cardiovascular health of the black South African population is a major health concern as this group suffers mostly from hypertension and stroke, leading to an alarming increase in cardiovascular morbidity and mortality. SuPAR may be able to contribute to early detection and prevention of cardiovascular diseases. No studies regarding the associations of suPAR with cardiovascular function have been investigated on black South Africans. Objectives To investigate suPAR as a possible marker of cardiovascular function in African and Caucasian men and women, by determining possible gender and ethnic–specific associations of suPAR with cardiovascular function. Methodology There were 207 African and 314 Caucasian men and women (aged 20–79 yrs.) included in this study. High–sensitivity C–reactive protein, glucose, lipids and creatinine were determined in fasting serum and suPAR was analyzed in plasma samples. Blood pressure was measured using the OMRON apparatus (HEM–747), with a 5–min rest interval between measurements. The Finometer device was used to determine the Windkessel compliance and the carotid dorsalis–pedis pulse wave velocity (PWV) was measured with the Complior (SP acquisition system) on the left side of each subject in the supine position. The means, adjusted means and proportions were compared between the groups by using independent t–tests, analysis of co–variance and the chi–square test, respectively. Associations were investigated between cardiovascular variables and suPAR using single and multiple regression analyses with either pulse wave velocity, systolic blood pressure, diastolic blood pressure or Windkessel compliance as dependent variable. Covariates included were age, body mass index, smoking, alcohol use, physical activity, glucose and high–density lipoprotein cholesterol. Results and conclusion SuPAR levels were significantly higher in Africans (P<0.001) compared to Caucasians. After adjusting for body mass index, suPAR increased significantly with age in all groups, except for African women. Moreover, the suPAR levels of African men and women were significantly higher than the Caucasians within each age quartile. While adjusting for age and body mass index, the cardiovascular profiles of the African and Caucasian men were less favourable compared to women, but suPAR levels were significantly higher in Caucasian women compared to men. In single regression, various measures of cardiovascular function correlated with suPAR in African men and Caucasian men and women. After adjusting for confounders the associations disappeared in Caucasian women, and remained nonsignificant in the African women. However, the association between PWV and suPAR remained significant in African men (B=0.19; P=0.030), while the association of systolic blood pressure (B=0.20; P=0.017), diastolic blood pressure (B=0.17; P=0.020) and Windkessel compliance (B=–0.14; P=0.004) with suPAR remained significant in Caucasian men. In conclusion, Africans presented higher suPAR levels compared to Caucasians, even when stratified by age. Gender specific associations indicated that suPAR was associated with arterial stiffness in African and Caucasian men only, therefore, indicating that suPAR could be a possible biomarker for predicting cardiovascular dysfunction. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2011.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

Thesis (M.S.P.H.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on Sept. 3, 2009). Includes bibliographical references (p. 43-48).

Class of 2006 Abstract / Objectives: To determine the cost-effectiveness of urokinase (UK) and alteplase (recombinant tissue plasminogen activator, rt-PA) when used intra-arterially for the treatment of acute peripheral arterial occlusions. Methods: A decision analytic model was constructed using TreeAge Pro 2005 Suite to determine the cost- effectiveness of these therapies. Data for costs and probabilities were collected from published literature, as well as other references. Average and incremental cost-effectiveness ratios were calculated with a 95% confidence interval. A two-dimensional (sampling plus trials) Monte Carlo analysis with 5,000 patients was performed, along with a sensitivity analysis of the costs and variables. The costs measured were direct medical costs from the perspective of the healthcare institution. The primary outcome variable assessed in this model was 30-day survival. Results: The Monte Carlo microsimulation indicated that average cost-effectiveness (C/E) ratio for rt-PA was $54,141 (95th CI: 44,647 to 62,832) per successful treatment, while the average C/E ratio for UK was $65,515 (95th CI: 56,286 to 76,135). The ICER for rt-PA versus UK as the baseline was calculated to be $284,170 per additional survival over 30 days (95th CI: 186,097 to 418,443). Neither strategy was dominant. Conclusions: This study found rt-PA to be less costly but also slightly less efficacious than UK for patients treated for acute arterial occlusions. Neither therapy was indicated to be dominant over the other in terms of 30-day survival. Further long-term outcome data is necessary to more extensively assess the benefits of each therapy.

La dépression majeure représente l’une des affections les plus lourdes dans le monde, touchant plus de 350 millions depersonnes. La 5e édition du Diagnostic and Statistical Manual of Mental Disorders (DSM-V) est la référence mondiale utiliséepour poser le diagnostic de la pathologie chez l’humain. Bien que très nombreux, les antidépresseurs prescrits à ce jour restentencore malheureusement inefficaces pour 30% des patients. Dans ce contexte, il est fondamental de développer de nouvellesstratégies thérapeutiques pour soigner les patients. Des études récentes suggèrent, sans toutefois le démontrer véritablement,l’implication de l’axe « activateur tissulaire du plasminogène / inhibiteur de l’activateur tissulaire du plasminogène de type 1 »(axe tPA/PAI-1) dans la pathogenèse de la dépression majeure.La première partie de mes travaux a été consacrée à la mise au point d’un nouveau système d’évaluation comportementalede la dépression majeure chez la souris en modélisant de manière exhaustive et standardisée les symptômes cliniques du DSMV.La seconde partie de mes travaux a consisté à étudier les mécanismes d’action potentiels de l’axe tPA/PAI-1 dans ladépression majeure. Pour ce faire, j’ai tout d’abord caractérisé le phénotype comportemental de souris déficientes en tPA (souristPA-/-) et en PAI-1 (souris PAI-1-/-), ainsi que de leurs homologues de type sauvage, grâce au système fonctionnel d’évaluationinitialement mis en place. Par ailleurs, du fait de la forte comorbidité entre anxiété et dépression, les comportements de typeanxieux ont également été analysés chez ces animaux. Mes expériences ont révélé un phénotype de type dépressif, indépendantdu tPA, chez les souris déficientes en PAI-1, associé à des diminutions des concentrations de deux monoamines (sérotonine etdopamine) dans des structures cérébrales connues pour être impliquées dans la dépression majeure (hippocampe et noyau du litde la strie terminale). De surcroît, l’enrichissement modéré de l’environnement n’amenuise pas les symptômes de type dépressifdes souris PAI-1-/- mais conduit cependant à la disparition des troubles anxieux dépendants, quant à eux, de l’axe tPA/PAI-1.La troisième partie de ma thèse a été dédiée à des manipulations pharmacologiques visant à tester l’efficacitéd’antidépresseurs de type inhibiteurs de la recapture de la sérotonine. L’escitalopram produit un effet anxiolytique chez les sourisdéficientes en PAI-1, sans toutefois contrebalancer le phénotype dépressif chez ces mêmes sujets. Qui plus est, la fluoxétine, àla même dose que l’escitalopram, est toxique pour ces souris.Les résultats de ma thèse apportent ainsi la première démonstration de l’implication de PAI-1 dans la dépression majeurepar un mécanisme indépendant de son interaction avec le tPA. Ces travaux démontrent également que la souris PAI-1-/- constitueun outil essentiel et innovant pour étudier les mécanismes cellulaires et moléculaires sous-jacents à la dépression majeure, ainsique pour la recherche de cibles thérapeutiques visant à améliorer l’efficacité des traitements. / Major depressive disorder is one of the heaviest mental disorders in the world, affecting more than 350 people worldwide.It is in the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) that the basis for an internationallyadmitted diagnosis was laid. Albeit diverse, existing antidepressants still remain ineffective for 30% of the patients. Under suchcircumstances, the necessity of developing new therapeutical strategies has arisen. Recent studies tend to suggest, withoutabsolute demonstration, the implication of the axis "Tissue Plasminogen Activator / Plasminogen Activator Inhibitor type-1"(tPA/PAI-1 axis) in the pathogenesis of major depressive disorders.The first section of my works has been devoted to the development of a new system of behavioural assessment in micefor depressive-like disorders, through a comprehensive and standardised modelling of clinical symptoms of DSM-V.The second section of my works has consisted in studying the potential action mechanisms of the tPA/PAI-1 axis in theemergence of depressive-like disorders. To do so, I first had to identify the behavioural phenotype of mice having from a tPA(tPA-/- mice) and PAI-1 (PAI-1-/-mice) deficiency as well as their wild-type counterparts through the system of assessment setup in the beginning of my research. In addition, due to the significant comorbidity between anxiety and depression, anxious-likebehaviours have been analysed as well. Among PAI-1-deficient mice, my experiments have disclosed a depressive-likephenotype, independent of tPA, and correlated with a decrease in the concentration of two monoamines (serotonin and dopamine)in brain structures known to be involved in major depressive disorder (hippocampus and bed nucleus of the stria terminalis).Besides, the moderate enrichment of the environment does not reduce the depressive-like symptoms of PAI-1-/- mice, yet inducesthe dissipation of dependent-tPA/PAI-1 axis anxious disorders.The third section of my PhD has been devoted to pharmacological experiments meant to assess the effectiveness ofantidepressants classified among selective serotonin reuptake inhibitors (SSRIs). Escitalopram produces anxiolytic falloutsamong PAI-1-deficient mice without for all that offsetting the depressive phenotype among these same mice. Moreover,fluoxetine administered in the same concentration as escitalopram has proven to be toxic for these mice.The results of these doctoral experiments have therefore demonstrated for the first time the implication of PAI-1 in theprocess of major depressive disorder through a mechanism independent from its interaction with tPA. These works have alsodemonstrated that PAI-1-/- mice make up a fundamental and cutting edge tool to study the cellular and molecular mechanismsunderlying major depressive disorder as well as to develop competent therapeutical targets intended to improve the efficiency oftreatments.

L’activateur tissulaire du plasminogène (tPA) est une sérine protéase initialement découverte dans le sang pour sa capacité à convertir le plasminogène en plasmine, une enzyme capable de dégrader les chaînes de fibrine des caillots sanguins. Pour cette fonction pro-fibrinolytique, le tPA est le seul traitement pharmacologique aujourd’hui utilisé dans la phase aiguë de l’accident vasculaire cérébral (AVC) de type ischémique, même s’il présente plusieurs limites. Outre son rôle dans la fibrinolyse, le tPA est aussi capable de moduler différents phénomènes physiologiques et pathologiques au sein du système nerveux central et de l’unité neurovasculaire, tels que la mémoire, l’excitotoxicité ou encore le couplage neurovasculaire comme décrit plus récemment. Plusieurs fonctions du tPA impliquent son interaction avec les récepteurs N-Methyl-D-Aspartate (NMDA), qui permet de potentialiser leur signalisation. Sur le plan structurel, deux formes du tPA ont été identifiées : une forme simple chaîne (sc-tPA) et une forme double chaîne (tc-tPA). Ces deux formes, dont les proportions peuvent varier dans la solution administrée aux patients pour la thrombolyse post-AVC ischémique, partagent certaines fonctions communes mais peuvent aussi avoir des actions différentes. Le premier objectif de nos travaux visait à mieux comprendre l’implication du tPA dans le couplage neurovasculaire, un phénomène essentiel au fonctionnement cérébral permettant aux régions en activité de bénéficier d’un apport accru en sang afin de subvenir à la demande énergétique des neurones. Dans une seconde partie, nous nous sommes intéressés aux effets des formes sc-tPA et tc-tPA utilisées lors de la thrombolyse dans un modèle murin d’AVC ischémique thromboembolique.Premièrement, nos résultats mettent en évidence la capacité du tPA vasculaire à augmenter l’hyperhémie fonctionnelle dans le cadre du couplage neurovasculaire. En effet, nous montrons chez la souris que le tPA vasculaire peut interagir avec les récepteurs NMDA présents à la surface des cellules endothéliales des artères et artérioles, et augmenter leur dilatation lors d’une activité neuronale. D’autre part, dans le cadre de l’ischémie cérébrale, nos résultats indiquent que lorsqu’ils sont utilisés pour la thrombolyse précoce, le sc-tPA et le tc-tPA ont des effets différents et parfois opposés. Le sc-tPA permet de réduire les volumes de lésion et d’améliorer la récupération fonctionnelle, alors que le tc-tPA est moins efficace pour réduire la lésion et ne diminue pas les déficits fonctionnels. De fait, nos données montrent que le tc-tPA aggrave l’altération de l’intégrité de la barrière hématoencéphalique par rapport au sc-tPA. Dans l’ensemble, ces données permettent d’améliorer les connaissances sur les mécanismes d’actions du tPA dans des phénomènes physiologiques et pathologiques importants. Nos travaux soulignent également la nécessité de prendre en compte les différences entre les formes de tPA dans l’amélioration du traitement actuel des AVC et dans l’élaboration de futures stratégies thérapeutiques impliquant cette molécule. / The tissue-type plasminogen activator (tPA) is a serine protease initially discovered in the blood for its ability to convert plasminogen into plasmin, an enzyme capable of degrading fibrin chains of blood clots. tPA is the only pharmacological treatment currently used for the acute phase of ischemic stroke, although it has several limitations. Besides its role in fibrinolysis, tPA also modulates various physiological and pathological phenomena within the central nervous system and neurovascular unit, such as memory, excitotoxicity and neurovascular coupling, which has been described recently. Several functions of tPA involve its interaction with N-Methyl-D-Aspartate (NMDA) receptors, which leads to an increase in NMDA signaling. Structurally, two forms of tPA have been identified: a single chain form (sc-tPA) and a double chain form (tc-tPA). These two forms, whose proportions vary in the solution administered for thrombolysis during ischemic stroke, share some common functions but may also differ in their therapeutic action. The first objective of our work was to better understand the implication of tPA in neurovascular coupling, which is an essential phenomenon for cerebral functioning that allows active brain regions to benefit from increased blood supply in order to meet local energy demands. In the second part of our work, we investigated the effects of sc-tPA and tc-tPA in a murine model of ischemic thromboembolic stroke.Our results establish a role for vascular tPA in increasing functional hyperemia in neurovascular coupling. We show that vascular tPA interacts with NMDA receptors present at the surface of endothelial cells of arteries and arterioles to increase their dilation during neuronal activity. In the context of cerebral ischemia, our results indicate that when administered during early thrombolysis, sc-tPA and tc-tPA have different and sometimes opposite effects. tc-tPA is less effective than sc-tPA in reducing lesion volume and protecting against functional impairment. In fact, our data show that tc-tPA worsens the integrity of the blood-brain barrier compared to sc-tPA. Overall, these data improve our knowledge of the mechanisms of action of tPA in important physiological and pathological phenomena. Our work underlines the need to take into account differences between sc-tPA and tc-tPA when trying to improve the current treatment for stroke and in the development of future therapeutic strategies involving this molecule.

L'anevrysme intracrânien (AIC) est une anomalie morphologique spécifique des artères cérébrales exposant au risque, particulièrement grave, de saignement intracrânien. Malgré les progrès établis dans le traitement curatif , aucun traitement préventif de la formation des AIC n’a été prouvé chez l’Homme. L’absence de traitement non invasif et l’absence de consensus sur le traitement des AIC non rompus sont le corolaire direct d’un manque de connaissance des mécanismes physiopathologiques de la maladie anévrysmale.L’ensemble du travail exposé ici a eu pour but de mieux comprendre les mécanismes de la pathologie anévrysmale intracrânienne pouvant être la base de nouvelles stratégies préventive améliorant le traitement des AIC.Nous avons tout d'abord étudié l'influence des anomalies du tissus de soutien des artères cervicales sur la formation des AIC. Au cours de cette étude, nous avons réalisé une étude cas-témoins dont l’objectif principal était d’étudier l’association entre les anomalies morphologiques des artères cervicales et la présence d’un AIC. Les objectifs secondaires étaient premièrement d’examiner si cette association variait selon le caractère rompu ou non de l’anévrisme et deuxièmement d’examiner si la sévérité des anomalies artérielles cervicales était liée à la sévérité de la pathologie anévrismale. Nous rapportons que la prévalence des anomalies angiographiques chez les patients porteurs d’AIC est élevée. De plus l’incidence d’une pathologie rare, la dysplasie fibro-musculaire est très élevée chez les patients porteurs d’AIC comparativement à la population générale. La présence des anomalies angiographiques n’a aucun impact sur l’évolution naturelle des AIC vers la rupture, ni sur d’autres aspect comme leur taille, leurs nombres ou leur forme. Dans le cadre de notre étude, nous pensons que l’association entre les anomalies angiographiques et les AIC semble être expliquée par l’hypothèse d'une vulnérabilité du tissu de soutien pariétal (condition pathologique particulière de la paroi artérielle à l’origine de la formation des AIC). Cette condition pathologique, affecterait de manière diffuse la vascularisation cérébrale et les artères cervicales. Les AIC seraient ainsi des manifestations cliniquement « bruyantes » de pathologies vasculaires plus silencieuses affectant la paroi de l’ensemble des vaisseaux. Les anomalies morphologiques des artères cervicales témoignent de façon sensible mais très peu spécifique de l’association des pathologies du tissu de soutien avec la présence d’AIC.Dans une deuxième partie nous essayons de décrire et de caractériser une voie inédite de la formation et de la croissance des AIC, la voie de la fibrinolyse via l'activateur de plasminogène de type tissulaire (tPA). Nos données suggèrent que le tPA présent dans la circulation sanguine est suffisant pour favoriser la formation et la rupture des anévrismes. Nous avons donc proposé que le tPA vasculaire était un des responsables de la formation des AIC. Nous avons également constaté une certaine continuité dans le temps de l'influence du tPA sur le remodelage matriciel. Nous avons donc proposé le tPA vasculaire comme une nouvelle cible possible pour prévenir la progression et la rupture des AIC. Différentes expériences ont été entreprise pour inhiber sélectivement le tPA et les résultats préliminaires sont encourageants et ouvrent la voie à une stratégie thérapeutique non invasive inédite. On peut aussi imaginer que ces différentes approches puissent être combinées entre elles et avec des agents matriciels ciblant directement l’activité du tPA dans la paroi des AIC. L’amélioration des stratégies thérapeutiques dans la pathologie anévrysmale intracrânienne est définitivement un axe de recherche dont les possibilités sont immenses et les résultats nécessaires et attendus. / Intracranial aneurysm (IA) is a specific morphological abnormality of the cerebral arteries that exposes to devastating intracranial bleeding. Despite the progress made in the curative treatment, no preventive treatment of IA formation has been proven in humans. The lack of non-invasive treatment and consensus on the treatment of unruptured IA are the consequences of the lack of knowledge of the physiopathological mechanisms of aneurysmal disease. All of the work presented here aims to better understand the mechanisms of intracranial aneurysmal pathology, which may be the basis of new preventive strategies improving the treatment of IA.We first studied the influence of cervical artery abnormalities on IA formation. In this study, we performed a case-control study whose main objective was to study the association between morphologic abnormalities of cervical arteries and the presence of IA. The secondary objectives were first to examine whether this association varied according to whether or not the aneurysm was broken, and secondly to examine whether the severity of the cervical arterial abnormalities was related to the severity of the aneurysmal pathology. We report that the prevalence of angiographic abnormalities in patients harboring IA is high. In addition, the incidence of a rare pathology, fibro-muscular dysplasia is very high in patients with IA compared to the general population. The presence of angiographic abnormalities has no impact on the rupture of the IA, nor on other aspects such as their size, numbers or shape. In our study, we believe that the association between angiographic abnormalities and IA seems to be explained by the hypothesis of a vulnerability of the arterial wall (a particular pathological condition of the arterial wall at the origin of IA formation). This pathological condition would affect the whole cerebral vasculature and cervical arteries. IA would thus be the clinical manifestations of more silent vascular pathologies affecting the wall of all vessels. The morphological abnormalities of the cervical arteries testify sensitively but not very specifically of the association of the arterial wall diseases with the presence of IA.In a second study, we try to describe and characterize an unprecedented pathway of formation and growth of IA : the pathway of fibrinolysis via tissue-type plasminogen activator (tPA). Our data suggest that tPA present in the bloodstream is sufficient to promote formation and rupture of aneurysms. We therefore proposed that vascular tPA was one of those responsible for training IA. We also noted a certain continuity in the time of the influence of the tPA on the matrix remodeling. We therefore proposed vascular tPA as a possible new target to prevent progression and rupture of IA. Various experiments have been undertaken to selectively inhibit tPA and the preliminary results are encouraging and open the way to an unprecedented non-invasive therapeutic strategy. It is also conceivable that these different approaches could be combined with each other and with matrix agents directly targeting tPA activity in the AIC wall. The improvement of therapeutic strategies in intracranial aneurysmal pathology is definitely an topic of ​​research whose possibilities are huge and the results necessary and expected.