There are well over 100,000 Americans on the kidney transplant list with a median wait time of 3.6 years. However, about 17 American die each day waiting for a kidney transplant, with vascular calcification being one of the most common causes [1, 2]. One vessel that is highly susceptible to vascular calcification is the aorta leading to negative cardiovascular outcomes that are secondary to kidney disease [3]. Therefore, understanding the effects that kidney disease has on disrupting the physiology of the vasculature, and finding potential therapeutic options, are imperative to those waiting for a life-saving kidney transplant. The present study aimed to test two hypotheses: (1) Aortic calcification leads to a decrease in stress in the thoracic and abdominal aorta of a young adult mouse. (2) The attenuated aortic stress seen in aortic calcification is due to the decreased expression of smooth muscle ⍺-actin (SM⍺-Actin). To test these hypotheses, calcification was induced in the ex vivo mouse aorta, followed by histological staining for calcium deposits, immunoblots for SM⍺-Actin, and measurements of aortic stress. The results of this study support the hypotheses in that calcification impairs aortic stress and it does so by decreasing the expression of SM⍺-Actin. The present study is the first to show the effect of phosphate-induced calcification on stress and expression of SM⍺-Actin in an ex vivo mouse aorta. This study is relevant to researchers as it shows key differences between studying vascular calcification in vitro compared to ex vivo. Therefore, investigating the mechanisms of aortic calcification using an ex vivo model, may be more applicable to human patients. / 2024-05-17T00:00:00Z

Background: Women are more likely to develop age-related cognitive impairment compared with men of the same age. Pregnancy complications, such as preeclampsia (PE), and menopause may contribute to an elevated risk of cognitive decline with aging in women potentially through an adverse impact on vascular function. PE is associated with a heightened risk of hypertension and large elastic artery stiffness (i.e., aortic and carotid arteries) for several years postpartum. Persistent large artery stiffness may be further amplified in women with a history of PE during the menopause transition, which is marked by an accelerated rate of vascular aging. However, large artery stiffness has not been studied extensively in postmenopausal women with a history of PE. Age-related elevations in large artery stiffness are associated with cognitive decline in middle-aged and older adults however, this relation has not been investigated in young women with a history of PE. Moreover, the degree to which elevated large artery stiffness is amplified and associated with reduced cognitive function among postmenopausal women with a history of PE remains unknown. The purpose of this study was to examine the extent to which large elastic artery stiffness is associated with reductions in cognitive function in premenopausal and postmenopausal women with a history of PE. Methods: Large elastic artery stiffness and domains of cognitive function were assessed in young women one year postpartum (n=18, ages 24-41 yrs.) and postmenopausal women (n=19, ages 52-77 yrs.) thirty-five years postpartum. Aortic stiffness was measured via non-invasive applanation tonometry at the carotid and femoral pulse sites and expressed as carotid-femoral pulse wave velocity (cfPWV). Carotid artery stiffness was quantified as beta-stiffness index (β-stiffness) was measured via ultrasonography and carotid tonometry. Cognitive tests were administered to assess cognitive function in immediate and delayed recall, working memory, processing speed, and executive function. Results: Premenopausal women with a history of PE had higher systolic blood pressure (121 ± 4 vs. 101 ± 3 mmHg, p =0.01) one year postpartum but did not differ significantly from controls in cfPWV (6.2 ± 0.4 vs. 5.1 ± 0.2 m/s, p =0.08), β-stiffness (6.1 ± 0.5 vs. 6.1 ± 0.7 U, p =0.97), or cognitive domains of memory, executive function, or processing speed (all p>0.05). Higher systolic blood pressure was associated with lower executive function (r = -0.53, p = 0.05) in young women one year postpartum. Postmenopausal women with a history of PE did not differ from controls in blood pressure, large artery stiffness, or age-adjusted cognitive domains of memory, executive function, or processing speed (all p>0.05). Large artery stiffness was not associated with cognitive function in premenopausal or postmenopausal women. Conclusions: Young women with a history of PE had elevated systolic pressure one year postpartum, which was associated with reductions in executive function. Large artery stiffness was not elevated or related to cognitive function in postmenopausal women with a history of PE. These preliminary findings suggest that young women with a history of PE are susceptible to reductions in selective cognitive domains related to higher blood pressure, but this effect does not appear to extend into the postmenopausal period.

Cardiovascular disease is the leading cause of human death worldwide. Currently, the prevalence of cardiovascular disease and health care costs associated with its onset continue to increase in both developed and developing societies. Concordant with the need to improve preventative measures is the imperative to develop more effective and efficient remedies for incident cardiovascular pathologies. Increased aortic stiffness with aging has recently emerged as an early, independent, and consistent physiological predictor of cardiovascular disease and represents an attractive target for possible therapeutic options. The success of any biomedical strategy in this regard is incumbent upon comprehension of biological processes and mechanical properties attributable to constituent components within the aortic wall. This dissertation tested the hypothesis that aging-induced changes to smooth muscle maintenance of biomechanical homeostasis within the aorta lead to undesirable increases in stiffness, correlative with increased risk of negative cardiovascular outcomes. Conventionally, mechanical studies and models have identified extracellular matrix as the primary determinant of changes in stiffness, but new research presented here shows that this may not be true. In viable ex vivo preparations of aortic tissue, roughly half of the maximal elastic modulus results from alpha-agonist activation of smooth muscle cells. Investigation of the biochemical interactions that characterize this effect revealed a link between aging and decreased expression of Src, a kinase involved in numerous signaling pathways governing cellular growth and survival, as well as defective regulation of focal adhesions between the smooth muscle cells and extracellular matrix. These findings were integrated into a model of aortic contractility and stiffness that establishes an aging-impaired regulatory complex comprising focal adhesions and non-muscle actin cytoskeleton in vascular smooth muscle cells. A better understanding of the mechanisms underlying this model may motivate the design of potential therapeutics, deliverable to previously overlooked target sites within aortic smooth muscle, and ultimately novel treatments for aging-induced cardiovascular disease. / 2017-10-27T00:00:00Z

Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention. Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers. Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age. Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p<0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10. Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI. Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers. Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.

L’augmentation de l’obésité durant les dernières décennies expose la population à un risque accru de problèmes métaboliques et des maladies cardiovasculaires. Ce travail étudiait, d’une part, l’association de l’obésité avec la dysfonction diastolique et la rigidité artérielle aortique vingt ans plus tard chez des adultes initialement en bonne santé. Cette étude montrait que l’obésité générale mesurée par l’indice de masse corporelle et l’adiposité abdominale mesurée par le tour de taille étaient associées positivement à la dysfonction diastolique. Mais elles semblaient jouer un rôle protecteur sur la rigidité artérielle. Le ratio “tour de taille/indice de masse corporelle” semblait mieux isoler l’adiposité abdominale/viscérale de l’obésité générale, et était associé positivement à la rigidité artérielle. Il permettrait de montrer un rôle néfaste à long terme de l’adiposité abdominale/viscérale sur la rigidité artérielle même quand le poids est normal. La présence combinée de l’obésité abdominale (mesurée par le tour de taille) et d’un taux plus élevé de triglycérides était associée à un risque élevé de dysfonction diastolique. Dans la deuxième partie, nous nous sommes intéressés aux individus ayant déjà une hypertension artérielle. Ce travail montrait que, parmi les sujets ayant une hypertension, ceux ayant une hypertension non-diagnostiquée avaient un profil spécifique (plus souvent de sexe masculin, un tour de taille moins élevé, et moins souvent de maladies cardiovasculaires/diabète, antécédents familiaux d’hypertension et consultations de soins primaires moins fréquents). La présence concomitante d’un nombre élevé de ces critères renforçait fortement l’absence de primo-diagnostic. Nos résultats peuvent aider dans l’identification précoce des sujets à risque, la prévention et le management thérapeutique / Worldwide increasing obesity over the last decades expose the population to an increased risk of metabolic perturbations and cardiovascular diseases. This research investigated first the association of obesity with diastolic dysfunction and aortic stiffness observed 20 years later in initially healthy adults. General obesity measured with body mass index and abdominal adiposity measured with waist circumference were positively associated with diastolic dysfunction. But, these anthropometric parameters played a protective role in aortic stiffness. The ratio “waist circumference / body mass index” appeared to better isolate abdominal adiposity from general obesity and was then positively associated with aortic stiffness. It allowed to evidence a harmful role of abdominal adiposity in aortic stiffness, even in subjects with normal body weight. The presence of abdominal adiposity (measured with waist circumference) combined with an elevated level of triglycerides was associated with a higher risk of diastolic dysfunction. In the second part, our research focused on hypertensive individuals. It showed that among hypertensive subjects, those having undiagnosed-hypertension had specific features (being more often male, having less elevated waist circumference, and having fewer cardiovascular diseases/diabetes, familial hypertension history, and primary care uses). The concomitant presence of a higher number of these criteria appeared to strongly reinforce the absence of diagnosis. Our findings may help to early identify subjects at risk, and to establish prevention and therapeutic management

La rigidité artérielle ayant une valeur prédictive forte et indépendante d'évènements cardiovasculaires, nous émettons l'hypothèse que l'accumulation de variations de contraintes hémodynamiques altère la fonction et la structure des gros troncs artériels, indépendamment du niveau de pression artérielle. Nous avons donc mesuré l'impact de la variabilité tensionnelle sur la rigidité et la structure artérielles dans différents modèles de variabilité tensionnelle chez le rat.Chez le rat barodénervé et le rat sympathectomisé par la guanéthidine, 2 modèles de variabilité tensionnelle à court terme, une augmentation de la rigidité artérielle est associée à des altérations tissulaires différentes. En effet chez les rats barodénervés, une hypertrophie aortique est couplée à une augmentation du collagène et des attachements cellule-matrice (fibronectine et intégrine α5). Au contraire, chez les rats sympathectomisés, une hypotrophie vasculaire est associée à une diminution de l'élastine et une augmentation des attachements via l'intégrine αv.Nous avons ensuite créé, caractérisé et validé un modèle de variabilité tensionnelle à long terme, le rat spontanément hypertendu traité de façon discontinue par un antihypertenseur. Le traitement discontinu réduit la pression artérielle systolique tout en augmentant isolément la variabilité tensionnelle à long terme. La rigidité artérielle, élevée sous traitement discontinu, est associée à une hypertrophie vasculaire avec augmentation des attachements (fibronectine et intégrine αv) et sans modification du rapport élastine/collagène.En conclusion, l'élevation de variabilité tensionnelle engendre de la rigidité artérielle, et ce à pression artérielle constante. Les altérations structurales dans les modèles de variabilité tensionnelle étudiés impliquent des mécanismes différents reposant sur des modifications des relations cellule-matrice, mettant en jeu la fibronectine et les intégrines α5 et αv. / Arterial stiffness is nowadays accepted as a strong and independent predictor of cardiovascular disease. We hypothesized that increased blood pressure variability (BPV) may lead to arterial damage, independently of the blood pressure level. We thus aimed investigating the relationship between BPV and arterial stiffness and composition of the aorta in different rat models of increased BPV.In a first study performed in two models of increased short term BPV, sinoaortic denervated and chemically sympathectomized rats, an increase in wall stiffness was associated with different modifications of cell-extracellular matrix adhesion. Indeed in sinoaortic denervated rats, increased media cross-sectional area was coupled with an increased collagen content and muscle cell attachments to its cell-extracellular matrix (fibronectin and its α5β1 integrin). In contrast, chemically sympathectomized rats were characterized by a reduced media cross-sectional area associated to a reduction of elastin content and upregulation of αvβ3 integrin.In a second study, we created, characterized and validated a new experimental model of long term BPV by discontinuously treating spontaneously hypertensive rats with valsartan. Discontinuous treatment reduced systolic blood pressure level but increased long term BPV. In addition, this treatment regimen failed to reduce arterial stiffness and induced a vascular hypertrophy without modification of elastin/collagen ratio. Discontinuous treatment also highly increased vascular fibronectin in parallel to αv integrin.In conclusion, a rise of both short- and long-term BPV leads to an increase in arterial stiffness, independently of blood pressure level. The structural changes at the origin of this increase in arterial rigidity involve different mechanisms, in which fibronectin and integrin α5 and αv play a key role.

Preeclampsia is one of the leading causes of maternal and fetal mortality and morbidity. Furthermore, women who have had preeclampsia have an increased risk of cardiovascular events over the next 10-15 years. Indeed, preeclampsia is associated with a four-fold increase in the risk of hypertension and double the risk of fatal and non fatal ischaemic heart disease and stroke. In addition, offspring born to preeclampsia are more likely to have higher blood pressure from childhood and stroke in later life. The risk to mother and offspring is greatest when preeclampsia is diagnosed at an earlier gestation, suggesting a more severe form of preeclampsia. As the long term cardiovascular risk to both mother and child is known from delivery, the main interest of my research was to identify key phenotypic variations in mothers and children during the years between the episode of preeclampsia and emergence of established cardiovascular disease, which might explain the link between the two conditions. This information could then be used to devise ways to identify subjects at greatest risk of later cardiovascular disease and to establish intermediate endpoints for future preventative interventions. Therefore, in a case control study, women diagnosed with preeclampsia between 1998 and 2003 and their offspring were recruited and underwent comprehensive cardiovascular and metabolic phenotyping. Furthermore, young adults born preterm to hypertensive pregnancy were also investigated in their twenties. The research demonstrates that early-onset preeclampsia, diagnosed before 34 weeks gestation, is associated with blood pressure patterns in mothers 6-13 years after pregnancy that are distinct from those seen following later-onset disease. Furthermore, there is evidence of distinct differences in cardiac, vascular and metabolic profiles in these individuals with women having evidence of increased arterial stiffness, changes in cardiac function and reduced capillary density. Preterm offspring of hypertensive pregnancies similarly have higher blood pressure than seen in those born following late-onset disease and, in young adult life, have reduced endothelial function and changes in cardiac size proportional to this dysfunction. This research demonstrates adverse cardiac and vascular remodelling after preeclampsia in mothers and offspring that are evident before the development of clinical cardiovascular disease. The identified differences in cardiac and vascular function may be useful as surrogate endpoints in future preventive trials.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-12T15:21:22Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de Zoraya versão definitiva 131015 aceita.pdf: 2706371 bytes, checksum: 83da3cf5bbbffb2d66214831901498f3 (MD5) / Made available in DSpace on 2016-04-12T15:21:22Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de Zoraya versão definitiva 131015 aceita.pdf: 2706371 bytes, checksum: 83da3cf5bbbffb2d66214831901498f3 (MD5) Previous issue date: 2015-02-27 / Esta tese teve como objetivo estudar um marcador de aterosclerose subclínica, a rigidez aórtica, medida através da velocidade de onda de pulso aórtica, diante da importância de se identificar os pacientes com risco maior de desenvolver doenças cardiovasculares (DCV), hoje, uma das principais causas de morbidade e mortalidade, não relacionada à síndrome da imunodeficiência adquirida (AIDS) em pessoas vivendo com o vírus da imunodeficiência humana (PVHIV). Entre setembro de 2011 e janeiro de 2013, a população do estudo composta por homens e mulheres vivendo com o vírus da imunodeficiência humana (HIV), participantes da coorte HIV/AIDS-PE, no nordeste do Brasil, iniciada em 2007, foi submetida a dois desenhos de estudos visando identificar os fatores de risco cardiovasculares tradicionais e emergentes associados com a rigidez aórtica e sua progressão.Visando identificar fatores de riscos cardiovasculares emergentes, incluindo a perda de massa óssea, realizamos um estudo transversal em mulheres vivendo com HIV que haviam realizado densitometria mineral óssea, no período entre Outubro de 2010 a Novembro de 2011. A densidade mineral óssea (DMO), foi medida pela absorciometria de energia dupla de raio-x de (DXA) nas regiões da coluna lombar, colo de fêmur e fêmur total e a rigidez aórtica, foi medida pela velocidade de onda de pulso aórtica (VOPa). O resultado principal deste estudo foi a correlação negativa significante entre a DMO do colo de fêmur e do fêmur total com a VOPa mesmo ajustada para idade, síndrome metabólica e pressão arterial média. Sugerindo que mulheres vivendo com HIV com perda de massa óssea deverão ser avaliadas para doença cardiovascular aterosclerótica. Para investigar a progressão da rigidez aórtica, foram acompanhados por uma média de 2,9 anos, homens e mulheres vivendo com HIV que haviam realizado a primeira avaliação da rigidez aórtica entre Abril e Novembro de 2009. O achado mais importante deste estudo foi a verificação de uma acelerada progressão da rigidez aórtica associada a fatores de risco tradicionais, idade, sexo masculino e hipertensão arterial e uma correlação negativa com a duração da infecção em uma população sob bom controle virológico. Os dados favorecem intensificar medidas para melhor controle da hipertensão arterial e da imunodeficiência. / This thesis aimed to study a marker of Subclinical Atherosclerosis, aortic stiffness measured by aortic pulse wave velocity, given the importance of identifying the patient with higher risk of developing cardiovascular diseases, today, one of the leading causes of morbidity and mortality, not related to AIDS. Between September 2011 and January 2013, the study population comprised of men and women living with human immunodeficiency virus (HIV), HIV/AIDS cohort participants-PE, in northeastern Brazil, initiated in 2007, have undergone two designs of studies aimed at identifying the factors of traditional and emerging cardiovascular risk associated with aortic stiffness and its progression. Aiming to identify emerging cardiovascular risk factors, including the loss of bone mass, we performed a cross-sectional study in women living with HIV who had performed bone mineral densitometry in the period between October 2010 to November 2011. Bone mineral density was measured by dual-energy x-ray absorptiometry (DXA) in regions of the lumbar spine, neck femur and total femur and aortic stiffness was measured by aortic pulse wave velocity (aPWV). The main result of this study was the significant negative correlation between the BMD of the femoral neck and total femur aPWV even adjusted for age, metabolic syndrome and mean arterial pressure. Suggesting that women living with HIV with low of bone mass should be assessed for atherosclerotic cardiovascular disease. To investigate the progression of aortic stiffness, were accompanied by an average of 2.9 years, men and women living with HIV who had carried out the initial evaluation of aortic stiffness between April and November 2009 .The most important finding of this study was the verification of an accelerated progression of aortic stiffness associated with traditional risk factors, age, male and hypertension and a negative correlation with duration of infection in a population under good viral control. The data favor the aggressive measures of intensify and immunodeficiency hypertension.

L’hypertension systolique isolée (HSI) est le résultat de changements au niveau de la paroi vasculaire qui ont pour conséquence d’augmenter la rigidité artérielle. Ces modifications surviennent surtout au niveau des grosses artères comme l’aorte et sont associées au vieillissement. La fragmentation des fibres élastiques, leur calcification (élastocalcinose) et la fibrose font partie des changements majeurs observés avec l’âge. En plus de ces changements, le vieillissement vasculaire provoque des modifications au niveau des cellules qui composent la paroi. Les cellules endothéliales sécrètent moins de monoxyde d’azote (NO) provoquant une dysfonction endothéliale et les cellules musculaires lisses vasculaires (CMLVs) synthétisent maintenant des protéines matricielles et osseuses. Situé entre le sang et les CMLVs, l’endothélium contrôle le tonus vasculaire par la sécrétion de plusieurs substances vasoactives qui interagissent entre elles afin de maintenir l’homéostasie du système vasculaire. Parmi celles-ci, on note l’endothéline (ET), un puissant vasoconstricteur et le NO, un gaz vasorelaxants. Ce dernier est aussi reconnu pour bloquer la production d’ET par un mécanisme dépendant du guanosine monophosphate cyclique (GMPc). Comme il y a une interaction entre le NO et l’ET, et que cette dernière est impliquée dans la calcification artérielle, le NO pourrait être impliqué dans la modulation de l’élastocalcinose et de la rigidité artérielle par l’inhibition de l’ET et la modification de la composition de la paroi. Cet effet, qui se produirait au delà des effets vasorelaxants du NO, offre un potentiel thérapeutique intéressant pour l’HSI. Afin d’évaluer l’implication du NO dans la calcification vasculaire et la rigidité artérielle, un modèle animal d’HSI a été utilisé (modèle warfarine vitamine K, WVK). Ce modèle d’élastocalcinose est basé sur l’inhibition de la maturation d’une protéine anti-calcifiante, la matrix Gla protein (MGP), par la warfarine. Afin de déterminer l’implication physiologique du NO dans l’initiation et la progression de l’élastocalcinose, sa production a été inhibée par un analogue de la L-arginine, le L-NG-nitroarginine methyl ester (L-NAME). Lors des processus d’initiation de la calcification, le L-NAME a prévenu l’élastocalcinose sans toutefois modifier la vitesse de l’onde de pouls (PWV). Suite au traitement L-NAME, l’expression de la NO synthase inductible (iNOS) a été diminuée alors qu’elle a été augmentée lors du traitement WVK. Elle pourrait donc être impliquée dans les processus de calcification vasculaire. De plus, la NO synthase endothéliale (eNOS) semble également impliquée puisqu’elle a été augmentée dans le modèle WVK. Cette hausse pourrait être bénéfique pour limiter l’élastocalcinose alors que l’expression de la iNOS serait délétère. Lors de la progression de la calcification, le L-NAME a augmenté l’élastocalcinose et le PWV. Dans ce contexte, l’ET serait impliquée dans l’amplification de la calcification vasculaire entrainant une hausse de la rigidité artérielle. Comme le NO endogène limite la progression de la calcification et conséquemment la rigidité artérielle, il semble être protecteur. L’efficacité d’une modulation de la voie du NO dans le modèle WVK a été étudiée par l’administration d’un donneur de NO, le sinitrodil, ou d’un inhibiteur de la phosphosdiestérase 5 (PDE5), le tadalafil. La modulation de la voie du NO semble être bénéfique sur la rigidité artérielle, mais seulement de façon aiguë. En effet, le sinitrodil a modifié de transitoirement la rigidité au niveau de l’aorte possiblement par la modulation du tonus vasculaire sans toutefois avoir des effets sur la composition de la paroi. Comme le modèle WVK n’affecte pas la fonction endothéliale, les concentrations endogènes de NO semblent être optimales puisque le sinitrodil provoque une augmentation de l’élastocalcinose possiblement par le développement d’une tolérance. Tout comme le sinitrodil, le tadalafil a modulé de manière aiguë la rigidité artérielle sans modifier la composition de la paroi. Globalement, ces travaux ont permis de mettre en évidence les effets bénéfiques du NO endogène pour limiter le développement de l’HSI, suggérant qu’une dysfonction endothéliale, tel qu’observé lors du vieillissement, a un impact négatif sur la maladie. / Isolated systolic hypertension (ISH) is the result of complex changes in the vascular wall and consequently the increase of arterial stiffness. These modifications occur mainly in conductance arteries, like the aorta, and are associated with aging. The fragmentation of elastic fibers, calcification (elastocalcinosis), and fibrosis are major changes with age. In addition to these changes in the extracellular matrix, vascular aging also induces vascular cell wall modifications. These include decreased production of nitric oxide (NO) by endothelial cells, which induces endothelial dysfunction, and the production of matrix and bone proteins by vascular smooth muscle cells (VSMCs). Located between the blood and VSMCs, the endothelium controls vascular tone by secreting various vasoactive factors. These factors interact with each other to maintain the hemodynamic of the vascular system. Among these factors, the vasoconstrictor endothelin (ET) and the vasodilator NO. The latter has been shown to block ET production via a cyclic guanosine monophosphates-(cGMP) dependent mechanism, whereas ET has been implicated in arterial calcification. Therefore, NO might be involved in the modulation of elastocalcinosis and arterial stiffness by inhibiting ET and modifying the vascular wall composition. This effect of NO could offer interesting therapeutic potential for ISH. To evaluate the implication of NO in the vascular calcification and arterial stiffness, an animal model of ISH was used. This model of elastocalcinosis is based on the inhibition of the maturation of the anti-calcific protein, matrix Gla protein (MGP), by warfarin (WVK model). To gain insight into the physiological role of endogenous NO in the initiation and progression of elastocalcinosis, its production was inhibited by the administration of L-NAME. Interestingly, elastocalcinosis was prevented by L-NG-nitroarginine methyl ester (L-NAME) administration without any modifications of the pulse wave velocity (PWV) during the initiation of the calcification processes. After the L-NAME treatment, the expression of inducible NO synthase (iNOS) was decreased, whereas upon treatment with warfarin alone the expression of iNOS was increased, which could be implicated in vascular calcification and arterial stiffness. In addition, endothelial NO synthase (eNOS) seems to be implicated in this process as its expression was also increased upon WVK treatment. This increase could be beneficial to limit elastocalcinosis, whereas the increase in iNOS expression could be harmful. L-NAME administration during the progression of calcification increased elastocalcinosis and PWV. In an endothelial dysfunction context, ET has been shown to be involved in the amplification process of vascular calcification causing an increase in arterial stiffness. As NO limits the progression of calcification and consequently arterial stiffness, endogenous NO seems to be protective in the aorta. The efficacy of exogenous modulation of the NO pathway in the WVK model was studied upon administration of the NO donor, sinitrodil, or the phosphodiesterase type 5 inhibitor (PDE5), tadalafil. The exogenous modulation of the NO pathway seemed to be beneficial for arterial stiffness, but only in an acute manner. Indeed, sinitrodil modified the acute stiffness in the aorta potentially by vascular tone modulation, without having any effect on vascular wall composition. Since endothelial function was not affected upon WVK model, endogenous NO concentrations seem to be optimal. Thus, exogenous NO potentially caused an increase of elastocalcinosis by inducing tolerance to NO. As well as sinitrodil, tadalafil modulated the arterial stiffness in an acute manner without modifying the composition of the vascular wall. Broadly, these studies provide evidence that endogenous NO can limit ISH development, suggesting that endothelial dysfunction, as observed in aging, has a negative impact on this pathology.

Elle peut être estimée par deux indices : la distensibilité de la paroi aortique et la vitessede propagation de l'onde de pouls (VOP) le long de l'artère. Ces marqueurs peuvent êtreobtenus dans l'aorte proximale grâce à l'imagerie de résonance magnétique (IRM) et sontreliés entre eux par le modèle de Bramwell-Hill. L'objectif de cette thèse est, d'une part, deproposer et de valider cliniquement des méthodes d'estimation de la distensibilité et de laVOP aortique, et, d'autre part, d'étudier le modèle théorique de Bramwell-Hill, au regarddes données cliniques. Nous avons dans un premier temps comparé différentes méthodesd'estimation de la distensibilité de l'aorte. Cette étude a permis d'identifier l'approche quifournit la meilleure description physiologique de l'aorte ascendante et descendante. Ensuite,nous avons proposé une nouvelle méthode de mesure de la VOP proximale. Celle-cia été validée par comparaison avec les méthodes proposées dans la littérature en termesde reproductibilité et de corrélations des mesures avec : 1) l'âge : facteur de risque "naturel " de la rigidité aortique chez des sujets sains, et 2) la VOP carotido-fémoralemesurée par tonométrie, méthode de référence utilisée en routine clinique pour estimer larigidité globale de l'aorte. Enfin, nous avons validé le modèle théorique de Bramwell-Hillau niveau des sections de l'aorte ascendante et descendante. En conclusion, nous avonsproposé des approches locale et régionale d'évaluation de la rigidité de l'aorte proximaleet nous en avons validé la robustesse, notamment dans le cadre du vieillissement artériel. / The aortic stiffness is recognized as a major factor of cardiovascular risk, and is characterizedby distensibility and pulse wave velocity (PWV) measurements. These aorticindices are related according to the Bramwell-Hill model and can be assessed in the proximalaorta with magnetic resonance imaging (MRI). The aims of this thesis were : 1) topropose and validate clinical methods for estimating the distensibility and aortic PWVfrom MRI data, and 2) to study the theoretical model of Bramwell-Hill in the light ofclinical data. First, we compared different methods for estimating the distensibility ofthe aorta. This study permitted to identify the approach which provides the best physiologicaldescription of the ascending and descending aorta. Then we proposed a newmethod for estimating the PWV in the proximal aorta, which was validated by comparisonwith previously described methods in terms of reproducibility and correlation ofaortic PWV with : 1) age : major risk factor of aortic stiffness in healthy subjects, and 2)carotid-femoral PWV measured by tonometry, gold standard method in clinical routinefor estimating the overall stiffness of the aorta. Finally, we validated the theoretical modelof Bramwell-Hill at the sections of the ascending and descending aorta. In conclusion, weproposed local and regional approaches to assess the stiffness of the proximal aorta, andwe validated its robustness, particularly in the context of aging.