The International Collaborative Study of Macronutrients, Micronutrients and Blood Pressure (INTERMAP) is a cross-sectional study investigating the role of macronutrients in blood pressure (BP). Data included four 24-hour dietary recalls; two 24-hour urine collections; eight BP readings; and questionnaire data for 4,680 men and women aged 40-59 years from 17 population samples in four countries (Japan, People's Republic of China, United Kingdo'm [UK], and United States of America [USA]). Aims were to (1) test the hypothesis that there ,. a direct relation of dietary starch intake to the systolic and diastolic BP of individuals; (2) explore associations of total carbohydrate (CHO) and subfractions with BP; (3) calculate dietary glycaemic index (GI) and glycaemic load (GL) for participants; and (4) explore associations of dietary GI and GL with BP. In multiple regression analyses, starch, total CHO, galactose and lactose intakes (% total energy, intake [TEl]) were inversely related to BP. Adjusting for non-dietary factors, sodium/potassium excretion and alcohol intake, the difference in systolic BP associated with 14.1% TEl (2 standard deviations) higher intake of starch was -1.2 (95% confidence intervals -2.2, -0.3) mmHg, while 16.3% higher total CHO intake was associated with a -1.3 (-2.2, :-0.3) mmHg difference. Among, UK and USA participants, 0.2% TEl higher galactose intake was associated with a -1.6 (-2.6, -0.6) mmHgdifference in systolic BP, while 3.6% TEl higher lactose intake was associated with a -1.9 (-3.0, -0.8) mmHg difference. Dietary GI and GL values were estimated for UK and Japanese participants, but were not associated with BP in regression analyses adjusted for multiple confounders. Low-order inverse associations between starch, total CHO, galactose, lactose and BP were observed. More research is needed from animal models, population studies, and randomised trials to determine if CHO intake has a role in the prevention and control of high BP.

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Hypertension is a major risk factor for heart disease and stroke. The National Institute for Health and Care Excellence (NICE) and international hypertension guidelines recommend measuring blood pressure (BP) in both arms during initial assessment of high blood pressure. This is not routinely done, and impracticality of the methods may be a reason for this. An inter-arm difference in blood pressure (lAD) is common and is important because: i. If undetected an inappropriately low BP is recorded with consequent underdiagnosis andlor under-treatment of hypertension. ii. lAD is associated with increased risk of cardiovascular morbidity and mortality. iii. Detecting lAD could identify people with peripheral arterial disease (PAD). It is assumed that an lAD is caused by localised upper limb PAD, but no direct evidence exists to support this; existing data is derived from selected groups with established vascular disease. Therefore this thesis by submission of papers aims to I. examine the strength of current evidence for an association of lAD with PAD and cardiovascular disease ii. explore the cross sectional and prospective associations of an lAD with cardiovascular morbidity and mortality in community cohorts representative of primary care populations, and iii. examine the utility of a single sequential pair of BP readings in predicting the presence or absence of a significant lAD measured by reference standard techniques. My systematic review findings showed that a systolic lAD ≥15mmHg was associated with PAD, pre-existing cerebrovascular disease and increased cardiovascular and all-cause mortality. These associations are confirmed in subsequent analyses of new cohorts representative of primary care populations with hypertension, diabetes, and in a large community cohort free of clinically evident vascular disease. Cross sectional associations with markers of vascular stiffness are examined and the aetiology of an lAD is explored. A single pair of measurements is shown to reliably exclude the presence of an lAD confirmed by the reference standard technique, suggesting that a pragmatic measurement technique could initially be employed in primary care. The implications of these findings are discussed and future areas of research identified.

Blood pressure is constantly changing due to internal and external influences. The body counteracts these changes via the baroreflex by altering heart rate, stroke volume and peripheral resistance. The integrity of the baroreflex is often measured by baroreflex sensitivity (BRS), the ratio of change in RR-interval to change in systolic pressure (SP). The simple model assumed by BRS is a black box, with an input, SP levels, and an output, RR-intervals, therefore BRS represents the gain of the system. If RR-intervals and SP levels are changing cyclically, for example in response to regular breathing, the phase offset between the input and output can also be measured.

High blood pressure is more common in black individuals of African origin than in other ethnic groups. It is thought that inherited differences in renal salt handling may, in part, account for the increased risk of high blood pressure in black individuals. The work in thesis aims to investigate the effects of both salt reduction and of a genetic polymorphism in one of the renal sodium handling mechanisms, the epithelial sodium channel (ENaC), on blood pressure and renal target organ damage in black individuals. The first clinical study in this thesis has examined the effects of modest salt reduction, from approximately 12 to 6 grams daily, on blood pressure and urine protein excretion in black hypertensives. Results show that salt reduction significantly reduces blood pressure and urine protein excretion. A further, much smaller, pilot study in black nohnotensiv~s demonstrated a small but significant fall in the mean 24hour systolic blood pressure following similar modest salt reduction. Further studies were conducted in order to explore the role of the T594M ENaC polymorphism on blood pressure in black individuals. We looked for evidence of ENaC over activity in the group that carried the T594M polymorphism. A case controlled study in black individuals with and without the polymorphism did not demonstrate any phenotypic differences between cases and controls. Data from the previous salt reduction study in black hypertensives was then re-analysed to determine if the T594M genetic status influenced the blood pressure response to salt. Numbers with the polymorphism in this study, however, were too small to demonstrate a significant difference between the two groups. A larger randomised controlled trial of amiloride and spironolactone in black hypertensives with and 4 • ) without the T594M polymorphism was also carried out and found no specific pharmacogenetic relationship between the T594M polymorphism and blood pressure response to amiloride.

The renin-angiotensin-aldosterone system (RAAS) is one of the major regulators of blood pressure. The actions and generation of RAAS components at the tissue level are less well appreciated. This work was designed to investigate the vascular wall not only as a target of the RAAS, but also as one of its sources. Immunocytochemical and immunoblotting analysis revealed positive renin immunoreactivity in the cytoplasm of cultured bovine aortic endothelial cells. Two immunoreactive bands of molecular mass approximately 37,000 and 40,000 dalton were identified. In situ hybridization confirmed that renin mRNA was localized in the same cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) using primers specific for human renin gave a clear single band with the predicted size for (pro)renin. These findings suggest that these vascular endothelial cells are a source of local synthesised renin. Conditioned medium from cultured bovine aortic endothelial cells (BAECCM) and rat aortic smooth muscle cells (RASMCCM) were shown to contain immunoreactive angiotensin II (Ang II) equivalent to 15.05 ± 4.67 pg/106 cells and 1 1.16 ± 1.8 pg/ 106 cells, respectively. Tritiated thymidine incorporation into aortic smooth muscle cells (ASMC) was increased by Ang II and by BAECCM. In both cases, this stimulated proliferation was inhibited by the Ang II type I (AT, ) receptor selective antagonist, losartan. Although tritiated thymidine uptake by rat aortic smooth muscle cells (RASMC) was not significantly enhanced by RASMCCM, it was significantly decreased by losartan in the presence of RASMCCM or of serum-free medium. Assay of RASMC proliferation by cell counting showed that the number of I cells in the presence of Ang II (10'6M) were nearly twice that in control cultures after r 2 days. These findings suggest that Ang II produced by ASMC locally may regulate ASMC growth in an autocrine or/and paracrine fashion, via the AT, receptor. RASMC was also shown to produce immunoreactive aldosterone. Ang II significantly enhanced aldosterone formation by RASMC. but not in the presence of losartan. Ang II stimulated 3H-thymidine uptake into RASMC was further enhanced by aldosterone, but inhibited by the aldosterone antagonist. spironolactone. and the 3ß-hydroxysteroid-dehydogenase inhibitor trilostane. These results suggest that the presence of locally generated aldosterone is essential for the stimulatory effects of Ang II, acting via the AT, receptor. on RASMC proliferation. Amplified products corresponding to transcripts of the CYP 11 BI gene were obtained by RT-PCR on RNA extracted from RASMC, using primers chosen from homologous parts of the exon I and exon 2 regions of CYP IIBI and CYP II B2 genes. Sequencing showed the presence of CYP 11 B1 transcript, but gave no evidence for CYP 11 B2 gene transcription. RT-PCR also gave a band corresponding to the 770 bp fragment from bases - 486 (upstream) to + 284 (exon 2) bp of the CYP 1lB1 gene. Furthermore, the present experiments demonstrated the transcription of the sequences 183-480 bp upstream from the CYP 11 B1 gene, and the use of competitive RT-PCR showed this was regulated by Ang 11. Thus. cultured RASMC may be the site of Ang 11 regulated transcription of a longer fragment of the CYP 11 B1 gene than generally expected. Finally, use of immunofluorescence and immunoblotting demonstrated the presence of an apparent binding carrier for 18-OH-DOC in cultured RASMC similar to that found in the rat adrenal.

L'hypertension artérielle pulmonaire (HTAP) est caractérisée par une atteinte progressive et chronique des vaisseaux pulmonaires entraînant une augmentation des résistances vasculaires pulmonaires. Mes travaux de doctorat ont eu pour but de comprendre l'implication des progéniteurs vasculaires dans le remodelage et dans la néomuscularisation des vaisseaux pulmonaires, caractéristique de l'HTAP. Une nouvelle population de cellules progénitrices positives pour le marqueur PW1, récemment identifiée dans les tissus adultes, a la capacité de se différencier en cellules musculaires lisses (CMLs). Notre hypothèse a donc été que cette population progénitrice pourrait être recrutée, se différencierait en CMLs et participerait ainsi au remodelage vasculaire au cours de l'HTAP. Nous avons mis en évidence la présence de trois populations progénitrices PW1+ dans le poumon de souris, capables de se différencier en CMLs vasculaires. Les cellules PW1+ sont résidentes et sont mobilisées dans 2 modèles d'HTAP; leur recrutement est précoce, dès 4j d'hypoxie chronique chez la souris ; le nombre de cellules PW1+ est augmenté chez le rat traité à la monocrotaline. Des résultats préliminaires suggèrent une implication des macrophages et de la voie CXCR4 dans ce recrutement des progéniteurs PW1+. Chez le patient HTAP, les cellules PW1+ sont très nombreuses dans les lésions artérielles et nous avons commencé à les isoler par FACS. Cette meilleure compréhension des mécanismes de mobilisation des progéniteurs vasculaires permet d'identifier des pistes thérapeutiques potentielles, et d'encourager à poursuivre les recherches sur ce versant cellulaire encore peu exploité dans cette maladie. / Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and neomuscularization. PW1+ progenitor cells were identified in various adult tissues and can differentiate in smooth muscle cells (SMC) in vitro. Our hypothesis was that PW1+ progenitor cells are recruited to participate in the vascular remodeling during PAH. PW1+ cells are localized in the lung parenchyma and in the perivascular zone in rodent and human lungs. Three resident myogenic PW1+ populations were identified in the mouse lung. After 4 days of CH, two of these PW1+ populations were significantly increased. The number of pulmonary proliferating PW1+ cells and the proportion of vessel-associated SMC derived from PW1+ cells were also significantly increased, attesting a recruitment and a differentiation of PW1+ cells into pulmonary vascular SMC during early chronic hypoxia-induced neomuscularization. Moreover, in the MCT-injected rat lungs, a severe PH model, the number of PW1+ cells was also increased. Preliminary data suggest that macrophages and CXCR4 axis are involved in the mobilization of PW1+ progenitor cells. In the human PAH lung, PW1+ cells were observed in remodeled vascular structures and seem increased as compared to control lung. A better understanding of vascular progenitor cells mobilization mechanisms will help determining the pathological pathways involved in the disease and identifying new potential therapeutic avenues.

L'administration chronique de rHuEPO peut engendrer de graves effets secondaires. Une augmentation de l’hématocrite provoquée par la rHuEPO, en augmentant l'érythrocytose, la viscosité sanguine et les forces de cisaillement à la surface vasculaire, peut être responsable d'hypertension artérielle (HTA) et de thromboses artérielles. La présence d'une fonction endothéliale normale et de monoxyde d'azote (NO) peut contrer les effets délétères thrombogène et hypertenseur de l'EPO. Sur ces bases, nous avons étudié les effets cardiovasculaires d'une administration chronique de rHuEPO dans différentes situations : dans le cadre du dopage, chezdes rats "sportifs" présentant une dysfonction endothéliale NO-dépendante induite par l'administration chronique de L-NAME et dans le cadre d'un traitement chez des rats urémiques développant une dysfonction endothéliale NO-dépendante résultante d'une néphrectomie de 5/6de la masse rénale. Chez nos rats entrainés, dopés et traités au L-NAME, nous avons observé une altération de la performance physique avec une mortalité importante (51%). Une HTA sévères'est développée chez ces rats, avec des valeurs de pression artérielle (> 220 mmHg) bien plusélevées que celles des rats recevant le L-NAME seul, associée à une altération de la vasorelaxation NO-dépendante aortique (< 60%). Les rats insuffisants rénaux (IRC) ont eux aussi montré une augmentation de la pression artérielle et une dysfonction endothéliale en réponse àl'acétylcholine au niveau de l'aorte et en réponse à une élévation du flux au niveau de l'artère mésentérique perfusée. Ces différents paramètres ont été améliorés par l'exercice. Les coupes de rein colorées au rouge Sirius ont montré une fibrose accentuée chez les rats CKD. La fibrose, la créatinémie et l'albuminurie ont été diminuées par l'exercice seul mais ont été aggravées chez les rats du groupe CKD+EPO+Ex. L'activité NADPH oxydase et l'expression des Nox4, p67phox etMAPK erk1/2 ont été augmentées chez les les rats CKD. L'exercice ou la rHuEPO ont prévenuces augmentations. Cependant, l'activité de la NAD(P)H oxydase et l’expression des MAPKerk1/2 sont restées élevées dans le rein des rats CKD+EPO+Ex. Nos données suggèrent que l'exercice seul a un effet protecteur contre les dysfonctions vasculaire et rénale et la fibrose rénale. Ces effets protecteurs sont associés à une inhibition de l'activité de la NADPH oxydase et des voies de signalisation MAPK erk1/2. Par contre, l'exercice combiné avec le traitement rHuEPO, a des effets délétères sur la structure et la fonction rénale des rats CKD. Ces effets nocifs semblent liés à la stimulation de la NADPH oxydase et des voies de signalisation MAPKerk1/2. Malgré les effets protecteurs cardiovasculaire et rénal de l'entraînement physique, ces résultats mettent en évidence que la fonction rénale peut être potentiellement endommagée ainsique la structure du rein en combinant l'exercice avec le traitement rHuEPO dans l'insuffisance rénale. En conclusion, nous pouvons dire que la rHuEPO affecte gravement la fonction cardiovasculaire du rat entraîné présentant une dysfonction endothéliale. Ce risque étant fatal,beaucoup de sportifs, voulant augmenter leur performance, mettent leur vie en danger. Par ailleurs, ayant remarqué les effets délétères au niveau rénal, en associant exercice et traitement rHuEPO dans des conditions expérimentales sur un modèle d'insuffisance rénale, nous suggérons une investigation clinique afin de vérifier la transposition de nos résultats aux patients insuffisants rénaux. / The chronic administration of rHuEPO can engender side effects. An increase of the hematocritinduced by rHuEPO, by increasing the erythrocytosis, the blood viscosity and the shear stress onvascular surface, can be responsible of arterial high blood pressure and arterial thrombosis. Thepresence of a normal endothelial function and nitric oxide (NO) can counter the noxious effectsof rHuEPO. On these bases, we studied the cardiovascular effects of a chronic administration ofrHuEPO in various frames: within doping field, to trained rats with L-NAME-induced NOdependentendothelial dysfunction and within the framework of a treatment, to chronic kidneydisease (CKD) rats developing endothelial dysfunction caused by the "5/6 nephrectomy". In ourdoped rats, we observed an important mortality (51%). A severe arterial high blood pressuredeveloped in these rats (> 220 mmHg) associated with an impairment of the NO-dependentvasorelaxation (< 60 %). CKD rats also showed an increase in blood pressure and an endothelialdysfunction, in response to acetylcholine in the aorta and in response to a rise in flow in perfusedmesenteric artery. These parameters were improved by exercise. Kidney sections stained withSirius red showed marked fibrosis in CKD rats. Fibrosis, creatinine and albumin were decreasedby exercise alone but were increased in rats from the CKD + EPO + Ex group. NAD(P)H oxidaseactivity and the expression of Nox4, p67phox, and MAPK erk1/2 were increased in CKDrats. Exercise or rHuEPO prevented these increases. However, the NAD(P)H oxidase activityand the expression of MAPK erk1/2 remained high in the kidney of rats from the CKD+EPO+Exgroup. Our data suggest that exercise alone has a protective effect against vascular and renaldysfunction and renal fibrosis. These protective effects are linked to the downregulation of theNADPH oxidase activity and MAPK erk1/2 signaling pathways. However, exercise combinedwith rHuEPO treatment has deleterious effects on kidney structure and function in CKDrats. These adverse effects appear to be related to the stimulation of NADPH oxidase and MAPKerk1/2 signaling pathways. Despite the cardiovascular and renal protective effects of physicaltraining, these results highlight the potentially damaging renal function and structure bycombining exercise with rHuEPO therapy in renal failure. In conclusion, we can say that therHuEPO affects seriously cardiovascular function in trained rat with endothelial dysfunction. Thisrisk being fatal, many sportsmen, looking to increase their performance, put their life in danger.Moreover, having noticed the deleterious effects in the kidney by combining exercise andrHuEPO therapy under experimental conditions on a model of renal failure, we suggest a clinicalinvestigation to verify the transposition of our results to patients with renal failure

La signalisation purinergique participe à de nombreux processus physiopathologiques dans le système cardiovasculaire. Alors que les nucléotides extracellulaires sont considérés comme des « signaux de danger » ; la NTPDase1(CD39), ectonucléotidase à l’origine de leur hydrolyse, permet de maintenir l’homéostasie vasculaire par ses actions anti-thrombotiques etimmuno-modulatrices. Le rôle de CD39 dans la fonction vasculaire liée à l’hypertension artérielle(HTA) reste méconnu. L’HTA, facteur de risque majeur de complications cardiovasculaires, est caractérisée par un remodelage structurel(hypertrophie, fibrose) et fonctionnel (hypercontractilité, dysfonction endothéliale) des vaisseaux, causées notamment par un stress oxydatif et une inflammation périvasculaire. L’objectif de notre projet a consisté à étudier l’évolution de CD39 ainsi que son rôle potentiel dans la condition vasculaire pathologique de l’HTA. Nous mettons en évidence une diminution de l’expression et de l’activité du CD39 vasculaire dans l’HTA. Une diminution de l’activité ADPase du CD39 soluble a également été observée au niveau circulant. L’étude des éléments à l’origine de cette diminution montre une sensibilité du transcrit vasculaire de CD39 à certaines cytokinespro- et anti-inflammatoires, mais également à une tension mécanique. Une étude in vivo du potentiel rôle de CD39 (souris déficientes pour le gène de CD39 (Entpd1) et traitement à l’apyrase) dans un modèle d’HTA à l’Angiotensine-II a également été réalisée. L’ensemble de ces données suggère qu’une diminution du CD39 vasculaire et circulant pourrait contribuer à majorer les altérations vasculaires contemporaines de l’HTA. / Purinergic signaling is involved in numerous physiopathological processes in cardiovascular system. While extracellular nucleotides are considered as « danger signals » ; the NTPDase1(CD39), ectonucleotidase responsible for their hydrolysis, preserves vascular homeostasis by itsanti-thrombotic and immunomodulatory actions.The role of CD39 in vascular function related to arterial hypertension remains unknown. Hypertension, the major risk factor of cardiovascular complications, is characterized by structural remodeling (hypertrophy, fibrosis) and functional (hypercontractility, endothelial dysfunction) of vessels caused in particular by perivascular oxidative stress and inflammation.Our aim was to investigate the evolution of CD39 expression / function and its potential contribution in the pathological vascular condition of hypertension. We highlighted a decrease invascular CD39 expression and activity in the context of hypertension. A decrease in soluble ADPase activity specific to CD39 was also observed in blood circulation. Investigation of elements responsible for this decrease reveals asensitivity of vascular CD39 transcription to several pro- and anti-inflammatory cytokines and to mechanical tension. In vivo study of potential role of CD39 (mice deficient for CD39 gene (Entpd1) and treatment with apyrase) in Angiotensin-II model of hypertension was also carried out. All these data suggest that a decrease in circulating and vascular CD39 may contribute to vascular changes associated with hypertension.