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Investigamos os efeitos do treinamento físico (T) aeróbio sobre o possível remodelamento de grandes artérias de animais hipertensos (SHR) e normotensos (WKY). Os animais foram submetidos à T em esteira (50-60% da capacidade máxima, 1h/dia, 5dias/semana) ou mantidos sedentários (S) por 3 meses. Ao final dos protocolos, foram submetidos à canulação crônica para registros hemodinâmicos basais. A seguir foram anestesiados e perfundidos com salina e PFA 4% para análise histológica e com solução Karnovski para microscopia eletrônica de transmissão (MET). A aorta torácica e abdominal e as artérias carótida, renal e femoral foram retiradas e processadas para a técnica de Weigert/Hematoxilina e MET. Na análise morfométrica foram determinados os seguintes parâmetros: DI, DE, espessura de parede, razão média/luz e AST de todos os segmentos arteriais, enquanto que na análise estereológica quantificou-se a densidade numérica (QA), a densidade volume (VV) e a densidade de área (SV) do núcleo do músculo liso vascular e do componente elástico (total, lamelar e fibrilar). Nos SHRS (vs WHYS) a PAM e FC basais apresentavam-se elevados (172±1 mmHg e 386±9 bpm, respectivamente). TF foi igualmente eficaz em aumentar o ganho de capacidade física em ambos os grupos (+264±12 e +279±33 m), mas quedas da PAM (-4%) e FC (-7%) foram observadas somente nos SHRT. Não foram observadas diferenças ultra-estruturais marcantes nos vasos de SHR e WKY, porém o T foi eficaz em reorientar as células musculares lisas, reduzir o colágeno da matriz extracelular, prevenir a duplicação da limitante elástica interna, reduzir a vacuolização subendotelial em ambos os grupos e prevenir a fragmentação da lâmina elástica interna na aorta torácica dos SHR. Nos SHRS vs WKYS houve aumentos significativos do calibre da aorta torácica (+7%), carótida (+19%), redução da abdominal (-7%) e aumentos da razão média/luz das artérias renal (+80%) e femoral (+48%). Houve também aumentos significativos de espessura e AST da carótida (+27% e +47% respectivamente), femoral (+64% e +62% respectivamente) e da aorta torácica (+31%). O T não causou alterações geométricas nas grandes artérias de SHR e de WKY, com exceção de aumento inesperado da razão média/luz na femoral (+31%, p<0,05) apenas nos SHRT. Quantos aos parâmetros estereológicos observou-se aumentos significativos na VV (+60%) e SV (+60%) do músculo liso vascular da aorta, acompanhados de redução significativa da VV (-10% e -29%) e SV (-11% e -23%) do componente elástico total e lamelar, sem alteração do componente elástico fibrilar nos SHRS. A razão entre densidade de volume de lamelas e fibrilas, densidade de volume do músculo liso vascular também foi significativamente reduzida (-43% e -56% respectivamente) nos SHRS. Por outro lado, o T determinou redução da QA (-25%), a VV (-40%) e SV (-40%) do músculo liso vascular apenas nos SHRT, sem alterar o componente elástico lamelar e fibrilar. No entanto, a razão componente elástico/músculo liso vascular foi corrigida pelo T (aumentos de +85% e +90%, respectivamente, vs SHRS). Nossos dados sugerem que a hipertensão aumenta preferencialmente a espessura das grandes artérias de forma a manter constante a tensão desenvolvida pela parede vascular, enquanto que o treinamento aeróbio de baixa intensidade, independente do nível de pressão arterial, modifica essencialmente o arranjo ultra-estrutural do vaso, determinando adicionalmente na artéria muscular esquelética alterações geométricas compensatórias a ajustes da microcirculação induzidos pelo exercício. Além disso, a comparação de nossos resultados com aqueles induzidos pelo treinamento na microcirculação muscular esquelética sugerem que os efeitos do T diferem entre grandes e pequenas artérias/arteríolas. / We investigated the effects of exercise training (T) on the possible remodeling of large arteries of spontaneously hypertensive (SHR) and normotensive rats (WKY). The animals were submitted to treadmill T (50-60% of maximum capacity, 1h/day, 5 d/week) or kept sedentary (S) for 3 months. At the end of the protocols, they were submitted to chronic cannulation for records of baselines hemodynamics. Following they were anesthetized and perfused with saline and PFA 4% for histological analysis and Karnovski solution for transmission electron microscopy (TEM). The thoracic and abdominal aorta and carotid, renal and femoral arteries were harvested and processed for the technique of Weigert/Hematoxylin and TEM. In morphometric analysis were determined the following parameters: DI, DE, thickness of wall, media/lumen ratio and AST in all arterial segments, while the stereological analysis quantified the density number (QA), the density volume (VV) and density of area (SV) of the nucleus of vascular smooth muscle and the elastic component (total, lamellar and fibrillar). In SHRS (vs WHYS) MAP and HR baseline were seen to be high (172 ± 1 mmHg and 386 ± 9 bpm respectively). T has also been effective in increasing the gain of physical capacity in both groups (+264 ± 12 and +279 ± 33 m), but falls in MAP (-4%) and HR (-7%) were observed only in SHRT. There were no significant ultrastructural differences in vessels of SHR and WKY, but T was effective in reorganize the smooth muscle cells, reduce the collagen of extracellular matrix, preventing the duplication of internal elastic lamina, reduce the subendothelial vacuolization in both groups and prevent the fragmentation of internal elastic lamina in the thoracic aorta of SHR. In SHRS there were significant increases in the caliber of the thoracic aorta (+7%) carotid (+19%), reduction of abdominal aorta (-7%), increases of the media/lumen ratio of the renal arteries (+80%) and femoral (+48%). There were also significant increases in thickness of the carotid and AST (+27% and +47% respectively), femoral (+64% and +62% respectively) and the thoracic aorta (+31%). T did not cause changes in the geometry of the large arteries of SHR and WKY, except for unexpected increase of media/lumen ratio in the femoral (+31%, p <0.05) only in SHRT. In spite of stereological parameters there were significant increases in VV (+60%) and SV (+60%) of the vascular smooth muscle of the thoracic aorta, with significant reduction of VV (-10%, -29%) and SV (-11 %, -23%) of the total and lamellar elastic component without changing the fibrillar elastic component in SHRS. The ratio between density of volume of lamellas and fibrils and density of volume of vascular smooth muscle was also significantly reduced (-43% and -56% respectively) in SHRS. Furthermore, T determined reduction of QA (-25%), VV (-40%) and SV (-40%) only in vascular smooth muscle in SHRT, without changing the lamellar and fibrillar elastic component. However, the ratio between elastic component and vascular smooth muscle cell was corrected by T (increases of +85% and +90% respectively, vs SHRS). Our data suggest that hypertension increases preferably the thickness of the large arteries in order to maintain constant tension developed by the vascular wall, while the low-intensity aerobic training, regardless of the level of blood pressure, changes essentially the ultrastructural arrangement of vessel, determining further, in skeletal muscle artery, geometric changes compensatory to adjustments of the microcirculation induced by exercise. Moreover, the comparison of our results with those induced by training in skeletal muscle microcirculation suggests that the effects of T differ between large and small arteries/arterioles.

Investigamos os efeitos do treinamento físico (T) aeróbio sobre o possível remodelamento de grandes artérias de animais hipertensos (SHR) e normotensos (WKY). Os animais foram submetidos à T em esteira (50-60% da capacidade máxima, 1h/dia, 5dias/semana) ou mantidos sedentários (S) por 3 meses. Ao final dos protocolos, foram submetidos à canulação crônica para registros hemodinâmicos basais. A seguir foram anestesiados e perfundidos com salina e PFA 4% para análise histológica e com solução Karnovski para microscopia eletrônica de transmissão (MET). A aorta torácica e abdominal e as artérias carótida, renal e femoral foram retiradas e processadas para a técnica de Weigert/Hematoxilina e MET. Na análise morfométrica foram determinados os seguintes parâmetros: DI, DE, espessura de parede, razão média/luz e AST de todos os segmentos arteriais, enquanto que na análise estereológica quantificou-se a densidade numérica (QA), a densidade volume (VV) e a densidade de área (SV) do núcleo do músculo liso vascular e do componente elástico (total, lamelar e fibrilar). Nos SHRS (vs WHYS) a PAM e FC basais apresentavam-se elevados (172±1 mmHg e 386±9 bpm, respectivamente). TF foi igualmente eficaz em aumentar o ganho de capacidade física em ambos os grupos (+264±12 e +279±33 m), mas quedas da PAM (-4%) e FC (-7%) foram observadas somente nos SHRT. Não foram observadas diferenças ultra-estruturais marcantes nos vasos de SHR e WKY, porém o T foi eficaz em reorientar as células musculares lisas, reduzir o colágeno da matriz extracelular, prevenir a duplicação da limitante elástica interna, reduzir a vacuolização subendotelial em ambos os grupos e prevenir a fragmentação da lâmina elástica interna na aorta torácica dos SHR. Nos SHRS vs WKYS houve aumentos significativos do calibre da aorta torácica (+7%), carótida (+19%), redução da abdominal (-7%) e aumentos da razão média/luz das artérias renal (+80%) e femoral (+48%). Houve também aumentos significativos de espessura e AST da carótida (+27% e +47% respectivamente), femoral (+64% e +62% respectivamente) e da aorta torácica (+31%). O T não causou alterações geométricas nas grandes artérias de SHR e de WKY, com exceção de aumento inesperado da razão média/luz na femoral (+31%, p<0,05) apenas nos SHRT. Quantos aos parâmetros estereológicos observou-se aumentos significativos na VV (+60%) e SV (+60%) do músculo liso vascular da aorta, acompanhados de redução significativa da VV (-10% e -29%) e SV (-11% e -23%) do componente elástico total e lamelar, sem alteração do componente elástico fibrilar nos SHRS. A razão entre densidade de volume de lamelas e fibrilas, densidade de volume do músculo liso vascular também foi significativamente reduzida (-43% e -56% respectivamente) nos SHRS. Por outro lado, o T determinou redução da QA (-25%), a VV (-40%) e SV (-40%) do músculo liso vascular apenas nos SHRT, sem alterar o componente elástico lamelar e fibrilar. No entanto, a razão componente elástico/músculo liso vascular foi corrigida pelo T (aumentos de +85% e +90%, respectivamente, vs SHRS). Nossos dados sugerem que a hipertensão aumenta preferencialmente a espessura das grandes artérias de forma a manter constante a tensão desenvolvida pela parede vascular, enquanto que o treinamento aeróbio de baixa intensidade, independente do nível de pressão arterial, modifica essencialmente o arranjo ultra-estrutural do vaso, determinando adicionalmente na artéria muscular esquelética alterações geométricas compensatórias a ajustes da microcirculação induzidos pelo exercício. Além disso, a comparação de nossos resultados com aqueles induzidos pelo treinamento na microcirculação muscular esquelética sugerem que os efeitos do T diferem entre grandes e pequenas artérias/arteríolas. / We investigated the effects of exercise training (T) on the possible remodeling of large arteries of spontaneously hypertensive (SHR) and normotensive rats (WKY). The animals were submitted to treadmill T (50-60% of maximum capacity, 1h/day, 5 d/week) or kept sedentary (S) for 3 months. At the end of the protocols, they were submitted to chronic cannulation for records of baselines hemodynamics. Following they were anesthetized and perfused with saline and PFA 4% for histological analysis and Karnovski solution for transmission electron microscopy (TEM). The thoracic and abdominal aorta and carotid, renal and femoral arteries were harvested and processed for the technique of Weigert/Hematoxylin and TEM. In morphometric analysis were determined the following parameters: DI, DE, thickness of wall, media/lumen ratio and AST in all arterial segments, while the stereological analysis quantified the density number (QA), the density volume (VV) and density of area (SV) of the nucleus of vascular smooth muscle and the elastic component (total, lamellar and fibrillar). In SHRS (vs WHYS) MAP and HR baseline were seen to be high (172 ± 1 mmHg and 386 ± 9 bpm respectively). T has also been effective in increasing the gain of physical capacity in both groups (+264 ± 12 and +279 ± 33 m), but falls in MAP (-4%) and HR (-7%) were observed only in SHRT. There were no significant ultrastructural differences in vessels of SHR and WKY, but T was effective in reorganize the smooth muscle cells, reduce the collagen of extracellular matrix, preventing the duplication of internal elastic lamina, reduce the subendothelial vacuolization in both groups and prevent the fragmentation of internal elastic lamina in the thoracic aorta of SHR. In SHRS there were significant increases in the caliber of the thoracic aorta (+7%) carotid (+19%), reduction of abdominal aorta (-7%), increases of the media/lumen ratio of the renal arteries (+80%) and femoral (+48%). There were also significant increases in thickness of the carotid and AST (+27% and +47% respectively), femoral (+64% and +62% respectively) and the thoracic aorta (+31%). T did not cause changes in the geometry of the large arteries of SHR and WKY, except for unexpected increase of media/lumen ratio in the femoral (+31%, p <0.05) only in SHRT. In spite of stereological parameters there were significant increases in VV (+60%) and SV (+60%) of the vascular smooth muscle of the thoracic aorta, with significant reduction of VV (-10%, -29%) and SV (-11 %, -23%) of the total and lamellar elastic component without changing the fibrillar elastic component in SHRS. The ratio between density of volume of lamellas and fibrils and density of volume of vascular smooth muscle was also significantly reduced (-43% and -56% respectively) in SHRS. Furthermore, T determined reduction of QA (-25%), VV (-40%) and SV (-40%) only in vascular smooth muscle in SHRT, without changing the lamellar and fibrillar elastic component. However, the ratio between elastic component and vascular smooth muscle cell was corrected by T (increases of +85% and +90% respectively, vs SHRS). Our data suggest that hypertension increases preferably the thickness of the large arteries in order to maintain constant tension developed by the vascular wall, while the low-intensity aerobic training, regardless of the level of blood pressure, changes essentially the ultrastructural arrangement of vessel, determining further, in skeletal muscle artery, geometric changes compensatory to adjustments of the microcirculation induced by exercise. Moreover, the comparison of our results with those induced by training in skeletal muscle microcirculation suggests that the effects of T differ between large and small arteries/arterioles.

Les antiangiogéniques (AAD) représentent une classe relativement récente d’anticancéreux indiqués dans un nombre croissant de cancers solides avancés. Ces traitements inhibent la voie du VEGF en amont avec le bevacizumab, un anticorps monoclonal dirigé contre le VEGF et en aval avec les inhibiteurs des tyrosines kinases des récepteurs impliqués dans cette voie de signalisation (sorafenib et sunitinib). Les AAD s’accompagnent d’effets secondaires dont le plus fréquent est l’hypertension artérielle. Ma thèse a pour objectif de mieux comprendre la physiopathologie de l’hypertension artérielle iatrogène induite par les AAD, notamment en mesurant l’effet des AAD sur les grosses artères. Le deuxième objectif est de déterminer des marqueurs précoces d’efficacité et d’optimisation de ces traitements, notamment avec un suivi thérapeutique pharmacologique (STP). Pour remplir ces objectifs nous avons mis en place une étude clinique prospective, observationnelle monocentrique dans laquelle nous avons suivi l’évolution de paramètres artériels au cours du traitement AAD avec des techniques non-invasives chez des patients atteints d’un cancer. Dans un premier travail nous avons montré qu’il y avait une augmentation précoce et cliniquement significative de la pression brachiale et centrale, de la rigidité artérielle et du diamètre carotidien sous AAD et que ces modifications étaient en partie indépendantes de la pression artérielle. Nous avons également montré que la présence d’ondes de réflexion amples et d’une rigidité aortique basse de base avant l’introduction des AAD prédisaient une augmentation de pression artérielle systolique (PAS) à un stade précoce d’exposition (coefficients de régression : 0.37[0.04-0.70] et -1.27[-2.43 ; -0.11], p<0.05 respectivement) alors qu’après une exposition chronique aux AAD, seule une rigidité artérielle basse de base prédisait une augmentation de la PAS (-2.46 [-4.02 ; -0.90], p<0.01). L’atteinte des grosses artères est positivement associée à l’évolution carcinologique. En effet une augmentation précoce de la rigidité aortique et carotidienne sous AAD étaient associées à un haut risque de progression (HR : 1.24 [1.01 ; 1.51], p=0.042 et 1.34 [1.03-1.73], p=0.027 respectivement). Dans la deuxième partie, nous avons montré à l’aide d’un modèle pharmacocinétique de population, que l’atteinte artérielle observée lors de la prise d’AAD était due à un effet pharmacologique des AAD sur les grosses artères indépendamment de l’augmentation de pression induite par les AAD. L’augmentation de rigidité artérielle était proportionnelle à la concentration plasmatique d’AAD et à l’augmentation de la pression artérielle (coefficient de corrélation standardisé : 0.37 et 0.35, p<0.01, respectivement), expliquant respectivement 13% et 11% de la variance. Nous avons également montré que la progression et la mortalité liées au cancer étaient moindre chez les patients les plus exposés aux AAD (HR : 0.60 [0.38 ; 0.97], p=0.035 et HR=0.38 [0.19-0.79], P=0.01 respectivement) et enfin, nous avons pu déterminer une concentration sérique cible qui permettra aux cliniciens d’avoir un objectif à atteindre pour optimiser l’efficacité des AAD. En conclusion, nous avons pu démontrer l’existence d’une atteinte précoce des grosses artères se traduisant par une augmentation de la rigidité artérielle et un remodelage carotidien sous traitement AAD. Cette atteinte artérielle est directement liée à un effet pharmacologique des AAD de manière indépendante de l’augmentation de pression induite par ces traitements. Nous avons montré que les altérations de la paroi artérielle ainsi que le suivi thérapeutique pharmacologique prédisaient le pronostic carcinologique. Le suivi des propriétés artérielles combinée au STP des AAD pourraient optimiser les chances d’efficacité de ces traitements. / Antiangiogenic drugs (AAD) are a relatively new class of anti-cancer therapy indicated in an increasing number of advanced solid tumors. By inhibiting the VEGF pathway, upstream with an anti-VEGF monoclonal antibody, bévacizumab, and downstream with tyrosine kinase inhibitors of receptors involved in this signaling pathway (sorafenib and sunitinib), AAD induce arterial hypertension which is the most common side effect. The principal objective of my thesis is to improve the understanding of the pathophysiology of hypertension induced by AAD, by determining the effect of AAD on large arteries. The second objective is to determine early marker of efficacy and optimization of AAD, by the use of therapeutic drug monitoring. To fulfill those objectives, we set up a clinical prospective, observational, single center study in which we followed the time-course of several arterial parameters after AAD by the use of non-invasive techniques in patients with metastatic solid tumors. In a first work we showed that brachial and central blood pressure, arterial stiffness and carotid diameter significantly increased after AAD, partly independently of blood pressure changes. We also showed that high reflection waves and low aortic stiffness at baseline (i.e. before AAD initiation) predicted early systolic blood pressure (SBP) increase (regression coefficients: 0.37[0.04; 0.70] and -1.27[-2.43; -0.11], P<0.05 respectively) while only low aortic stiffness predicted SBP increase after chronic AAD exposure (-2.46 [-4.02 ; -0.90], P<0.01). Large arteries damage under AAD is positively associated with cancer progression. Indeed, early increase of aortic and carotid stiffness after AAD were associated with a higher risk of cancer progression (HR: 1.24 [1.01; 1.51], P=0.042 and 1.34 [1.03; 1.73], P=0.027 respectively). In a second part, using a pharmacokinetic model of population, we showed that large arteries damage observed after AAD was partly due to a pharmacological effect of AAD on large arteries independently of blood pressure increase. Arterial stiffness increase was proportional to AAD blood concentration and blood pressure increase (standardized correlation coefficients: 0.37 and 0.35, P<0.01, respectively), explaining 13% and 11% of the variance respectively. We also showed that progression and mortality related to cancer were lower in patients high AAD blood concentrations (HR: 0.60 [0.38; 0.97], P=0.035 and HR=0.38 [0.19; 0.79], P=0.01 respectively). And finally, we determined a target AAD blood concentration which will allow the clinicians to have an objective to reach in order to optimize the efficacy of AAD. In conclusion, we were able to demonstrate the existence of large arteries damage translated by large arteries stiffening and a remodeling of carotid artery after AAD. This arterial damage is directly related to a pharmacological effect of AAD independently of blood pressure changes induced by these treatments. We showed that infringement of the arterial wall and the therapeutic drug monitoring predicted tumor prognosis. Thus, the monitoring of arterial properties monitoring and the therapeutic drug monitoring might optimize the chances of efficiency of AAD.

Cardiovascular disease varies by ethnicity in the UK. South Asians (SA) have higher coronary heart disease (CHD) and diabetes prevalence, while African-Caribbeans (AfC) have greater stroke, but intriguingly lower CHD rates despite higher blood pressures and diabetes risk than Europeans. Conventional risk factors do not fully explain such differences. This cross-sectional study tested the hypothesis that the hormones, vitamin D measured as 25(OH)D and aldosterone, would be independently associated with intermediate cardiovascular outcome markers in these ethnic groups. Community-dwelling men 40-80 years old (AfC: n=67, 55±10yr; SA: n=68, 55±10yr; European: n=63, 57±8yr) were sampled from Greater Manchester’s multi-ethnic population. The intermediate markers examined were aortic pulse wave velocity (aPWV), left ventricular (LV) mass and function, and carotid intima media thickness (CIMT), measured non-invasively by ultrasound, and hemodynamic profiling methods (the Arteriograph) in the total sample and by magnetic resonance imaging (MRI) in a subsample of 50. Adjusted for age, systolic blood pressure and diabetes, mean(SE) aPWV by the Arteriograph, was 0.5(0.2) m/s higher in SA than AfC and Europeans (p=0.01), which paralleled known cross-ethnic CHD risk differences in the UK. By MRI, aPWV along the descending aorta in SA was 0.7(0.3) and 0.8(0.3) m/s higher than that in AfC and Europeans, but aPWV along the aortic arch was not significantly different. Unlike aldosterone, 25(OH)D was independently and inversely correlated with aPWV (unstandardised B(SE)=-0.013[0.004] m/s, p<0.001), and partly explained the ethnic variation in aPWV. Similar inverse correlations were found between 25(OH)D and LV concentricity measured by echocardiography and MRI. Compared to Europeans, SA and AfC, had 21(3) and 14(3) nmol/L lower mean(SE) 25(OH)D, respectively (p<0.01). Mean(SE) of relative wall thickness, an index of LV concentricity by echocardiography, was 0.05(0.01) higher in SA and AfC than Europeans. Lower 25(OH)D levels were also associated with higher myocardial deformation rates measured by MRI myocardial tagging (n=50), supporting previous animal experimental evidence. A one standard deviation (SD) decrease in 25(OH)D was associated with a 0.38 SD increase in absolute systolic strain rate (p=0.003) and 0.22 SD rise in diastolic strain rate (p=0.04). Right and left CIMT showed different relations with 25(OH)D and aldosterone. Left-right CIMT differences varied by ethnicity and were related to SA ethnicity and aldosterone levels. Two related technical studies investigated the relatively new method of hemodynamic profiling, the Arteriograph, used here. The results suggested a standardisation method of aortic length estimation for purely central aPWV, which significantly improved aPWV agreement between the Arteriograph and MRI (reference method here), and was used for calibrating the Arteriograph aPWV in the above-mentioned results for the total sample. Future well-designed trials are necessary to investigate any cause-effect relationship between vitamin D deficiency and the unfavourable cardiovascular intermediate outcomes found here in a cross-sectional design and multi-ethnic background.