Contexte L’américanisation des habitudes de vie, notamment de l’alimentation, semble être en grande partie responsable de l’augmentation incessante de l’incidence élevée des maladies cardiovasculaires. La période postprandiale, où l’homéostasie vasculaire et métabolique est mise à l’épreuve, est d’une importance considérable dans le développement ou la prévention de l’athérosclérose et représente maintenant la majeure partie du temps d’éveil. La compréhension de l’influence de la composition d’un repas sur son impact postprandial est donc essentielle dans notre lutte dans la prévention de ces maladies. Objectifs L’objectif principal de ce projet de recherche était d’étudier les réponses endothéliale et métabolique à un repas de type méditerranéen mixte (MMM), puisqu’elles sont inconnues. Ce projet avait aussi pour objectifs d’évaluer l’impact microvasculaire d’un tel repas et de caractériser la composition postprandiale des acides gras plasmatiques. À titre comparatif, ces éléments ont aussi été étudiés suite à un repas riche en gras saturés (HSFAM). Méthodes Vingt-huit (28) hommes sains, exempts de facteurs de risque de maladies cardiovasculaires ont reçu de façon randomisée les deux repas à l’étude. Le MMM, composé de saumon frais et de légumes cuits dans l'huile d'olive, contenait 7.87g de SFA et 2.29g d’acides gras polyinsaturés oméga-3, tandis que le HSFAM, composé d'un sandwich déjeuner avec œuf, saucisse et fromage, contenait 14.78g de SFA. Les mesures de la fonction endothéliale mesurée par échographie brachiale (FMD), de la fonction microvasculaire mesurée par spectroscopie proche de l’infrarouge (NIRS) et de la composition des acides gras plasmatique ont été effectuées à jeun et en période postprandiale. Résultats Deux sous-groupes de répondeurs aux repas à l’étude se sont dégagés de ces travaux. Un premier sous-groupe de sujets ayant une triglycéridémie à jeun élevée, mais normale (hnTG) a démontré des altérations endothéliales seulement suivant le repas HSFAM. Un second sous-groupe de sujets ayant une triglycéridémie plus faible et normale (lnTG) n’a quant à lui pas subi d’altérations endothéliales suivant les deux repas à l’étude. Les sujets hnTG ont aussi démontré une charge triglycéridémique postprandiale (iAUC) plus importante et qui était de surcroît enrichie en acide stéarique suivant la HSFAM et en acide gras polyinsaturés oméga-3 suivant le MMM. L’évaluation par NIRS de la fonction microvasculaire nous révèle un ralentissement de la réoxygénation post-ischémique qui suggère une altération postprandiale du recrutement capillaire chez les sujets hnTG seulement. De telles altérations, qui semblent être plus importantes suivant le HSFAM, pourraient être en partie responsables de l’impact endothélial de ce repas. Conclusions Cet essai clinique démontre donc de façon novatrice qu’un repas MMM n’a pas d’effet endothélial délétère et que cette neutralité est indépendante de la triglycéridémie à jeun. De plus, une triglycéridémie à jeun élevée mais normale semble indiquer des dysfonctions endothéliales et métaboliques à des épreuves nutritionnelles tel un repas HSFAM. La consommation de repas méditerranéens par des individus sains à la triglycéridémie marginale serait bénéfique, peut-être même davantage que pour des individus de triglycéridémie plus faible, dans la prévention de l’athérogénèse et des maladies cardiovasculaires. / Background The Westernization of lifestyles, notably dietary habits, seems to be largely responsible for the ongoing increase of incidence of cardiovascular diseases. The postprandial period, where vascular and metabolic homeostatic regulating processes are under pressure, is of considerable importance in the development or prevention of atherosclerosis and now represents the majority of waking hours. The understanding of the postprandial effects of meals of varying composition is therefore essential in our effort to prevent such diseases. Objectives The main objective of this research project was to study the endothelial and metabolic responses to a mixed Mediterranean meal (MMM), since they are unknown. This project also aimed to evaluate the microvascular impact of such a meal and to characterize the composition of postprandial plasma fatty acids. These elements were also evaluated following a saturated fatty meal (HSFAM) for comparison. Methods Twenty-eight (28) healthy men free of cardiovascular diseases and risk factors were randomly assigned one of two test meals. The MMM, consisting of fresh salmon and vegetables cooked in olive oil, contained 7.87g of SFA and 2.29g of omega- 3 fatty acids, while the HSFAM, consisting of a breakfast sandwich with egg, sausage and cheese contained 14.78g of SFA. Evaluations of endothelial function by brachial ultrasound (FMD), of microvascular function by near-infrared spectroscopy (NIRS) and of plasma fatty acids composition were done in the fasted and postprandial states. Results Two subgroups of responders to the test meals emerged from this work. A first subgroup of subjects with high-normal fasting triglyceridemia (hnTG) experienced impairments of endothelial function following the HSFAM while a second subgroup of subjects with low-normal triglyceridemia (lnTG) did not experience any endothelial alterations following this meal. Interestingly, the MMM had no deleterious endothelial impact in any of those subgroups. Moreover, the hnTG subjects demonstrated greater postprandial triglyceridemic load (iAUC) that was in addition enriched with stearic acid after HSFAM and omega-3 PUFA following the MMM. Assessment of microvascular function revealed postprandial prolongation of post-ischemic reoxygenation only in hnTG subjects suggestive of alterations of capillary recruitment. These changes, which seemed to be more important after the HSFAM, could be partly responsible for its negative impact on FMD. Conclusions This clinical trial demonstrates in innovative ways that a MMM has no deleterious effects on endothelial function irrespective of triglyceridemia in normal ranges. In addition, high but normal fasting triglyceride levels suggest metabolic and endothelial dysfunctions following nutritional challenges such as a HSFAM. Consumption of Mediterranean meals by healthy individuals with marginal triglyceride levels would be beneficial, perhaps even more so than for individuals with lower triglyceride levels, in preventing atherogenesis and cardiovascular diseases.

No description available.

Dados sobre a avaliação não invasiva da rigidez vascular e suas relações com variáveis de risco cardiovascular são escassos em jovens. Objetiva avaliar a relação entre a velocidade de onda de pulso (VOP) e a pressão arterial (PA), variáveis antropométricas, metabólicas, inflamatórias e de disfunção endotelial em indivíduos adultos jovens. Foram estudados 96 indivíduos (51 homens) do Estudo do Rio de Janeiro, em duas avaliações, A1 e A2, com intervalo de 17,691,58 anos (16 a 21 anos). Em A1 foram avaliados em suas escolas (10-15 anos - média 12,421,47 anos) e em A2 foram novamente avaliados em nível ambulatorial (26-35 anos - média 30,091,92 anos). Em A1 foram obtidos pressão arterial (PA) e índice de massa corporal (IMC). Em A2 foram obtidos a velocidade da onda de pulso (VOP)-método Complior, PA, IMC, circunferência abdominal (CA), glicose, perfil lipídico, leptina, insulina, adiponectina, o índice de resistência à insulina HOMA-IR, proteína C-Reativa ultrassensível (PCRus) e as moléculas de adesão E-selectina, Vascular Cell Adhesion Molecule-1(VCAM-1) e Intercellular Adhesion Molecule-1 (ICAM-1). Foram obtidos, ainda, a variação da PA e do IMC entre as 2 avaliações. Em A2 os indivíduos foram estratificados segundo o tercil da VOP para cada sexo. Como resultados temos: 1) Os grupos foram constituídos da seguinte forma: Tercil 1:homens com VOP < 8,69 m/s e mulheres com VOP < 7,66 m/s; Tercil 2: homens com VOP &#8805; 8,69 m/s e < 9,65m/s e mulheres com VOP &#8805; 7,66 m/s e < 8,31m/s;Tercil 3:homens com VOP &#8805; 9,65 m/s e mulheres com VOP &#8805; 8,31 m/s. 2) O grupo com maior tercil de VOP mostrou maiores médias de PA sistólica (PAS) (p=0,005), PA diastólica (PAD) (p=0,007), PA média (PAM) (p=0,004), variação da PAD (p=0,032), variação da PAM (p=0,003), IMC (p=0,046), variação do IMC (p=0,020), insulina (p=0,019), HOMA-IR (p=0,021), E-selectina (p=0,032) e menores médias de adiponectina (p=0,016), além de maiores prevalências de diabetes mellitus/intolerância à glicose (p=0,022) e hiperinsulinemia (p=0,038); 3) Houve correlação significativa e positiva da VOP com PAS (p<0,001), PAD (p<0,001), PP (p=0,048) e PAM (p<0,001) de A2, com a variação da pressão arterial (PAS, PAD e PAM) (p<0,001) entre as duas avaliações, com o IMC de A2 (p=0,005) e com a variação do IMC (p<0,001) entre as duas avaliações, com CA (p=0,001), LDLcolesterol (p=0,049) e E-selectina (p<0,001) e correlação negativa com HDLcolesterol (p<0,001) e adiponectina (p<0,001); 4)Em modelo de regressão múltipla, após ajuste do HDL-colesterol, LDLcolesterol e adiponectina para sexo, idade, IMC e PAM, apenas o sexo masculino e a PAM mantiveram correlação significativa com a VOP. A VOP em adultos jovens mostrou relação significativa com variáveis de risco cardiovascular, destacando-se o sexo masculino e a PAM como importantes variáveis no seu determinismo. Os achados sugerem que a medida da VOP pode ser útil para a identificação do acometimento vascular nessa faixa etária. / Data on non-invasive evaluation of vascular stiffness in the young and its relationship with cardiovascular (CV) risk variables are scarce. Objective to assess the relationship between pulse wave velocity (PWV) and blood pressure (BP), anthropometric, metabolic, inflammatory and endothelial dysfunction variables in young adults. Ninety-six individuals (51 males) from The Rio de Janeiro Study cohort were studied in two evaluations, A1 and A2, with an interval of 17.69 1.58 years (16-21 years). In A 1 they were evaluated at their schools (10-15 years average 12.42 1.47 years) and in A2 they were all re-evaluated as outpatients (26-35 years - average 30.09 1.92 years). In A1 BP and body mass index (BMI) were obtained. In A2 pulse wave velocity (PWV) by Complior method, BP, BMI, waist circumference (WC), glucose, lipid profile, leptin, insulin, adiponectin, the HOMA-IR insulin resistance index, high sensitive C-Reactive protein (CRPhs) and E-selectin, Vascular Cell Adhesion Molecule 1 (VCAM-1) and Intercellular Adhesion Molecule 1 (ICAM-1) adhesion molecules were obtained. The BP and BMI variation over the time interval between the two evaluations were also obtained. Subjects were stratified according to tertile of PWV for each sex in A2. As results: 1) The groups were constituted as follows: Tertile 1: males with PWV <8.69 m/s and females with PWV <7.66 m/s; Tertile 2: males with PWV &#8805; 8.69 m/s and <9.65 m/s and females with PWV &#8805; 7.66 m/s and <8.31 m/s; Tertile 3: males with PWV &#8805; 9.65 m/s and females with PWV &#8805; 8.31 m/s 2) The group with the highest PWV tertile showed higher values of systolic BP (SBP) (p=0.005), diastolic BP (DBP) (p=0.007), mean BP (MBP) (p=0,004), DBP variation (p=0,032), MBP variation (p=0.033), BMI (p=0.046), BMI variation (p=0.020), insulin (p=0.019), HOMA-IR (p=0.021), E-Selectin (p=0.032) and lower values of adiponectin (p=0.016), besides higher prevalence of diabetes mellitus/glucose intolerance (p=0.022) and hyperinsulinemia (p=0.038); 3) There were a significant positive correlation of PWV with SBP (p<0,001), DBP (p<0,001), PP (p=0,048) and MBP (p<0,001) from A2, variation in blood pressure (SBP, DBP, and MBP) (p<0,001) between the two assessments, BMI (p=0.005) and BMI variation between the two evaluations (p<0,001), WC (p=0.001), LDL-cholesterol (0.049), and E-selectin (p<0,001) and negative correlation with HDL-cholesterol (p<0,001) and adiponectin (p<0,001); 4) In the multiple regression model, HDL-cholesterol, LDL-cholesterol and adiponectin lost statistical significance after adjustment for sex, age, BMI and MBP, only the male gender and MBP remained significantly correlated with PWV. PWV in young adults showed a significant association with CV risk variables, highlighting the male gender and MBP as important variables in its determining. The findings suggest that measurement of PWV can be useful for the identification of vascular impairment in this age group.

Dados sobre a avaliação não invasiva da rigidez vascular e suas relações com variáveis de risco cardiovascular são escassos em jovens. Objetiva avaliar a relação entre a velocidade de onda de pulso (VOP) e a pressão arterial (PA), variáveis antropométricas, metabólicas, inflamatórias e de disfunção endotelial em indivíduos adultos jovens. Foram estudados 96 indivíduos (51 homens) do Estudo do Rio de Janeiro, em duas avaliações, A1 e A2, com intervalo de 17,691,58 anos (16 a 21 anos). Em A1 foram avaliados em suas escolas (10-15 anos - média 12,421,47 anos) e em A2 foram novamente avaliados em nível ambulatorial (26-35 anos - média 30,091,92 anos). Em A1 foram obtidos pressão arterial (PA) e índice de massa corporal (IMC). Em A2 foram obtidos a velocidade da onda de pulso (VOP)-método Complior, PA, IMC, circunferência abdominal (CA), glicose, perfil lipídico, leptina, insulina, adiponectina, o índice de resistência à insulina HOMA-IR, proteína C-Reativa ultrassensível (PCRus) e as moléculas de adesão E-selectina, Vascular Cell Adhesion Molecule-1(VCAM-1) e Intercellular Adhesion Molecule-1 (ICAM-1). Foram obtidos, ainda, a variação da PA e do IMC entre as 2 avaliações. Em A2 os indivíduos foram estratificados segundo o tercil da VOP para cada sexo. Como resultados temos: 1) Os grupos foram constituídos da seguinte forma: Tercil 1:homens com VOP < 8,69 m/s e mulheres com VOP < 7,66 m/s; Tercil 2: homens com VOP &#8805; 8,69 m/s e < 9,65m/s e mulheres com VOP &#8805; 7,66 m/s e < 8,31m/s;Tercil 3:homens com VOP &#8805; 9,65 m/s e mulheres com VOP &#8805; 8,31 m/s. 2) O grupo com maior tercil de VOP mostrou maiores médias de PA sistólica (PAS) (p=0,005), PA diastólica (PAD) (p=0,007), PA média (PAM) (p=0,004), variação da PAD (p=0,032), variação da PAM (p=0,003), IMC (p=0,046), variação do IMC (p=0,020), insulina (p=0,019), HOMA-IR (p=0,021), E-selectina (p=0,032) e menores médias de adiponectina (p=0,016), além de maiores prevalências de diabetes mellitus/intolerância à glicose (p=0,022) e hiperinsulinemia (p=0,038); 3) Houve correlação significativa e positiva da VOP com PAS (p<0,001), PAD (p<0,001), PP (p=0,048) e PAM (p<0,001) de A2, com a variação da pressão arterial (PAS, PAD e PAM) (p<0,001) entre as duas avaliações, com o IMC de A2 (p=0,005) e com a variação do IMC (p<0,001) entre as duas avaliações, com CA (p=0,001), LDLcolesterol (p=0,049) e E-selectina (p<0,001) e correlação negativa com HDLcolesterol (p<0,001) e adiponectina (p<0,001); 4)Em modelo de regressão múltipla, após ajuste do HDL-colesterol, LDLcolesterol e adiponectina para sexo, idade, IMC e PAM, apenas o sexo masculino e a PAM mantiveram correlação significativa com a VOP. A VOP em adultos jovens mostrou relação significativa com variáveis de risco cardiovascular, destacando-se o sexo masculino e a PAM como importantes variáveis no seu determinismo. Os achados sugerem que a medida da VOP pode ser útil para a identificação do acometimento vascular nessa faixa etária. / Data on non-invasive evaluation of vascular stiffness in the young and its relationship with cardiovascular (CV) risk variables are scarce. Objective to assess the relationship between pulse wave velocity (PWV) and blood pressure (BP), anthropometric, metabolic, inflammatory and endothelial dysfunction variables in young adults. Ninety-six individuals (51 males) from The Rio de Janeiro Study cohort were studied in two evaluations, A1 and A2, with an interval of 17.69 1.58 years (16-21 years). In A 1 they were evaluated at their schools (10-15 years average 12.42 1.47 years) and in A2 they were all re-evaluated as outpatients (26-35 years - average 30.09 1.92 years). In A1 BP and body mass index (BMI) were obtained. In A2 pulse wave velocity (PWV) by Complior method, BP, BMI, waist circumference (WC), glucose, lipid profile, leptin, insulin, adiponectin, the HOMA-IR insulin resistance index, high sensitive C-Reactive protein (CRPhs) and E-selectin, Vascular Cell Adhesion Molecule 1 (VCAM-1) and Intercellular Adhesion Molecule 1 (ICAM-1) adhesion molecules were obtained. The BP and BMI variation over the time interval between the two evaluations were also obtained. Subjects were stratified according to tertile of PWV for each sex in A2. As results: 1) The groups were constituted as follows: Tertile 1: males with PWV <8.69 m/s and females with PWV <7.66 m/s; Tertile 2: males with PWV &#8805; 8.69 m/s and <9.65 m/s and females with PWV &#8805; 7.66 m/s and <8.31 m/s; Tertile 3: males with PWV &#8805; 9.65 m/s and females with PWV &#8805; 8.31 m/s 2) The group with the highest PWV tertile showed higher values of systolic BP (SBP) (p=0.005), diastolic BP (DBP) (p=0.007), mean BP (MBP) (p=0,004), DBP variation (p=0,032), MBP variation (p=0.033), BMI (p=0.046), BMI variation (p=0.020), insulin (p=0.019), HOMA-IR (p=0.021), E-Selectin (p=0.032) and lower values of adiponectin (p=0.016), besides higher prevalence of diabetes mellitus/glucose intolerance (p=0.022) and hyperinsulinemia (p=0.038); 3) There were a significant positive correlation of PWV with SBP (p<0,001), DBP (p<0,001), PP (p=0,048) and MBP (p<0,001) from A2, variation in blood pressure (SBP, DBP, and MBP) (p<0,001) between the two assessments, BMI (p=0.005) and BMI variation between the two evaluations (p<0,001), WC (p=0.001), LDL-cholesterol (0.049), and E-selectin (p<0,001) and negative correlation with HDL-cholesterol (p<0,001) and adiponectin (p<0,001); 4) In the multiple regression model, HDL-cholesterol, LDL-cholesterol and adiponectin lost statistical significance after adjustment for sex, age, BMI and MBP, only the male gender and MBP remained significantly correlated with PWV. PWV in young adults showed a significant association with CV risk variables, highlighting the male gender and MBP as important variables in its determining. The findings suggest that measurement of PWV can be useful for the identification of vascular impairment in this age group.

Au cours du vieillissement, la rigidification des artères élastiques entraine une augmentation de l'amplitude de la pression pulsée centrale, qui se propage dans la microcirculation cérébrale. De façon chronique, l’élévation anormale de la pression pulsée endommage les fonctions vasculaires et cérébrales, pouvant être impliquée dans le développement d’une déficience cognitive d’origine vasculaire. Ceci est supporté par l’observation d’anomalies cérébrovasculaires chez les individus atteints de démence vasculaire et de la maladie d’Alzheimer. De plus, les individus exposés aux facteurs de risque vasculaires (hypertension, obésité, diabète, athérosclérose), démontrent une vascularisation fragilisée, une augmentation de la pression pulsée centrale et présentent un déclin cognitif. Il est donc probable qu’en association avec l’âge, les facteurs de risque vasculaires favorisent de façon mécanistique la propagation de la pression pulsée dans la circulation cérébrale et révèlent de façon prématurée le déclin cognitif. Le lien mécanistique entre l’augmentation de la pression pulsée cérébrale, les facteurs de risque vasculaires, les dommages cérébrovasculaires et l’incidence de la démence reste à être plus clairement investigué. La présente thèse vise ainsi à étudier l’hypothèse biomécanique du rôle délétère de la pression pulsée dans la détérioration des fonctions cérébrovasculaires et cognitives, avec l’âge et en association avec les facteurs de risque vasculaires, en élucidant la cascade des événements pathologiques depuis l’élévation de la pression pulsée centrale jusqu’à l’incidence de la démence. Afin de vérifier notre hypothèse, nous avons entrepris dans une première étude d’étudier chez la souris WT, l’impact de l’augmentation in vivo d’un stress mécanique pulsatile central (par chirurgie TAC) sur la vasculature cérébrale, le tissu cérébral et les fonctions cognitives. Ce stress a été induit en parallèle dans le modèle de souris transgénique APP/PS1 de la maladie d’Alzheimer. Nous avons pu démontrer que les vaisseaux cérébraux des souris WT et APP/PS1 sont vulnérables au stress mécanique de la pression pulsée, caractérisé par une diminution de la réponse vasodilatatrice des artères piales, une raréfaction des capillaires due à une apoptose, l’incidence de micro-hémorragies, une rupture de la barrière hémato-encéphalique et une hypoperfusion cérébrale. Ces dommages cumulatifs à la microcirculation cérébrale sont associés à une inflammation cérébrale et à une diminution des performances d’apprentissage et de mémoire de travail et spatiale des souris. De plus, le phénotype Alzheimer des souris APP/PS1 est exacerbé en présence du stress vasculaire, exprimé par l’augmentation des dépôts béta-amyloïdes, ainsi que la dysfonction endothéliale cérébrale et l’inflammation cérébrale déjà présentes dans ce modèle. Dans une deuxième étude, nous avons caractérisé les fonctions cérébrovasculaires et cognitives des souris transgéniques LDLR-/-;hApoB100+/+ avec l’ajout ou non d’un stress mécanique pulsatile central in vivo (par chirurgie TAC). Ces souris présentent des facteurs de risques des maladies cardiovasculaires (hypertension et dyslipidémie) menant au développement d’athérosclérose et miment un vieillissement artériel central accéléré (rigidité aortique et des carotides, dysfonction endothéliale, augmentation de la pression pulsée). Nous avons démontré que les souris LDLR-/-;hApoB100+/+ exhibent des anomalies cérébrovasculaires structurelles et fonctionnelles, dont une atrophie cérébrale, une dysfonction endothéliale cérébrale, une hypoperfusion cérébrale, une augmentation de la perméabilité de la barrière hémato-encéphalique, des micro-hémorragies corticales, la présence d’inflammation, de sénescence et de stress oxydant au niveau vasculaire et parenchymateux. L’ensemble de ces altérations majoritairement vasculaires, sont associées à une diminution des performances cognitives et sont exacerbées en présence d’un stress vasculaire additif. Nos deux études chez la souris démontrent qu’en présence d’une pression pulsée élevée, les dommages à la microvasculature cérébrale conduisent à une perte fonctionnelle de l’homéostasie cérébrale et à un déclin cognitif, dont l’incidence est accélérée soit dans un modèle de démence ou soit de vieillissement artériel central et en présence de facteurs de risque des maladies cardiovasculaires. Nos études fournissent la démonstration mécanistique d’un continuum entre une augmentation de pression pulsée et un déclin cognitif vasculaire. / With advancing age, the large elastic arteries undergo significant stiffening, resulting in increased central pulse pressure waves that penetrates deeper the cerebral microcirculation and may result in cerebrovascular and neuronal tissue damages, likely contributing to the development of cognitive impairment from vascular injury origin. This is compatible with strong evidence between impaired cerebrovascular structure and function in the brain of patients with vascular dementia or Alzheimer’s disease. In addition, elderly individuals are subjected in their lifetime to multiple vascular risk factors (hypertension, obesity, diabetes, atherosclerosis), all of which are known to be deleterious to the vascular function, are associated with an increase in central pulse pressure and with cognitive decline. Therefore, it is likely that with age, risk factors for vascular diseases may mechanistically promote the propagation of pulse pressure into the cerebrovascular system and reveal prematurely the brain susceptibility to cognitive decline. The present thesis was conducted to study the biomechanical hypothesis of the deleterious role of the pulse pressure in the deterioration of cerebrovascular and cognitive functions, with age and in association with vascular risk factors, by elucidating the cascade of pathological events linking the increase in central pulse pressure to the expression of dementia. To validate our hypothesis, we first studied in mice the impact of the in vivo increase of central pulsatile mechanical stress (achieved by trans-aortic constriction surgery) on the cerebral vasculature, brain tissue and cognitive functions. This stress was also induced in the APP/PS1 transgenic mouse model of Alzheimer's disease. We have shown that cerebral vessels of WT and APP/PS1 mice are vulnerable to the mechanical stress of the increased pulse pressure, which is characterized by a decrease in the vasodilatory response of the pial arteries, a rarefaction of the capillaries due to apoptosis, the incidence of micro-hemorrhages, a rupture of the blood-brain barrier and cerebral hypoperfusion. These cumulative damages to the cerebral microcirculation are associated with brain inflammation and poorer learning and working and spatial memory performances in mice. The Alzheimer's phenotype of APP/PS1 mice was exacerbated in the presence of elevated pulse pressure, as shown by the increase in beta-amyloid deposits, the decreased in endothelial cerebral vasodilatory responses and brain inflammation, which are already present in this model. In a second study, we sought to characterize the cerebrovascular and cognitive functions in the transgenic mouse model LDLR-/-;hApoB100+/+, subjected or not in vivo to a central pulsatile mechanical stress (by trans-aortic constriction surgery). These mice exhibit risk factors for cardiovascular diseases (hypertension and dyslipidemia), develop atherosclerosis and mimic premature central arterial aging (aortic and carotid stiffness, endothelial dysfunction, increased pulse pressure). We reported that LDLR-/-;hApoB100+/+ mice were characterized by structural and functional brain vascular abnormalities, including cerebral hypoperfusion, increased permeability of the blood-brain barrier, endothelial cerebral dysfunction, microhemorrhages, but also cerebral atrophy and the presence of inflammation, senescence and high oxidative stress at the vascular and parenchymal level. In addition, all these alterations, which are mainly vascular, were associated with a decrease in the cognitive performance of mice. Also, these vascular, parenchymal and cognitive changes were exacerbated in the presence of the vascular stress induced by transverse aortic constriction. Altogether, our two studies in mice demonstrated that, in the presence of an increase in pulse pressure, the damages to the micro-cerebrovascular system lead to loss of cerebral homeostasis and to cognitive decline, which are accelerated in a model of dementia or a model of central vascular aging and in presence or vascular risk factors. Our studies highlight the mechanistic demonstration of a continuum between an increase in pulse pressure and vascular cognitive decline.