Titre de l'écran-titre (visionné le 11 janvier 2024) / La popularité grandissante de l'étude de la rigidité aortique dans les dernières décennies a permis une meilleure compréhension des maladies cardiovasculaires, qui restent à ce jour la première cause de décès dans les pays développés. En raison de la forte corrélation entre la rigidité aortique, l'âge et la survie, la rigidité aortique est devenue un excellent marqueur biomécanique du vieillissement vasculaire. Toutefois, des travaux plus récents ont montré que le gradient de rigidité artérielle qui intègre le rapport de rigidité périphérique sur la rigidité aortique expliquait davantage les dommages aux organes et était un meilleur prédicteur de morbidité et de mortalité cardiovasculaire. En effet, les artères musculaires périphériques sont physiologiquement plus rigides que l'aorte ce qui permet une atténuation de l'onde de pouls et protège ainsi la microcirculation d'une pression pulsatile élevée. Dans le but de mieux comprendre la biomécanique artérielle, nous avons tenté de manipuler de façon pharmacologique le gradient de rigidité artérielle. Étant donné les différences de compositions des parois artérielles de chaque segment, nous avons émis l'hypothèse que l'administration aiguë de nitroglycérine (NTG) pouvait modifier le gradient de rigidité artérielle par un effet plus significatif sur les artères musculaires moyennes, mesuré par la vélocité d'onde de pouls (VOP). Nous avons donc examiné l'impact différentiel de la NTG sur la rigidité régionale et le gradient de rigidité artérielle mesuré par le rapport VOP aortique-brachial (AB-VOP) et aortique-fémoral (AF-VOP).Nos travaux ont démontré que l'administration aiguë de NTG réduisait la VOP des artères musculaires (brachiale et fémorale) sans modifier la VOP aortique, résultant en une altération défavorable des rapports AB-VOP et AF-VOP, ce qui pourrait conduire à une transmission de pression pulsée plus élevée vers la microcirculation. Ce travail souligne l'importance de prendre en considération les rigidités segmentaires périphériques dans l'évaluation de la rigidité artérielle afin de développer une approche intégrée de l'arbre artériel et de sa réponse aux différents traitements. / The increasing interest of aortic stiffness in the last decades has allowed a better understanding of cardiovascular diseases, which remains to this day the leading cause of death in developed countries. Due to the strong correlation between aortic stiffness, age and survival, aortic stiffness has become an excellent biomechanical marker of vascular aging. However, more recent work has shown that the arterial stiffness gradient, which incorporates the ratio of peripheral arterial stiffness to aortic stiffness, further explains organ damage and is a better predictor of cardiovascular morbidity and mortality. Indeed, the peripheral muscular arteries are physiologically more rigid than the aorta, which allows an attenuation of the pulse wave and thus protects the microcirculation from a high pulsatile pressure. In order to obtain a better understanding of arterial biomechanics, we attempted to pharmacologically manipulate the arterial stiffness gradient. Given the differences in the composition of the arterial walls of each segment, we hypothesized that the acute administration of nitroglycerin (NTG) could alter the gradient of arterial stiffness through a more significant effect on the regional stiffness of medium-sized muscular arteries, measured by the pulse wave velocity (PWV). We therefore examined the differential impact of NTG on regional stiffness and arterial stiffness gradient measured by aortic-brachial PWV ratio (AB-PWV) and aortic-femoral PWV ratio (AF-PWV). Our work demonstrated that the acute administration of NTG reduced the PWV of the muscular arteries (brachial and femoral) without modifying the aortic PWV, resulting in an unfavorable alteration of the AB-PWV and AF-PWV ratios, which could lead to the transmission of a higher pulse pressure to the microcirculation. This work emphasizes the importance of taking peripheral segmental stiffness into consideration when evaluating arterial stiffness with the aim of developing an integrated approach to the arterial tree and its response to different treatments.

Organic nitrates, such as nitroglycerine (NTG), are widely used for their potent vasodilator capacity in the management of coronary artery disease and heart failure. Unfortunately, their beneficial effect is rapidly lost due to the development of nitrate tolerance, which is translated by an impaired vasorelaxation to NTG and an increased oxidative stress production. Although the mechanisms of the development of nitrate tolerance are still not fully elucidated, much interest has been focused in treating nitrate-receiving patients together with other drugs in order to overcome the development of nitrate tolerance. The Nitric Oxide generating enzyme, eNOS, and the superoxide anion generating enzyme, NAD(P)H oxidase, have been suggested to play a role in the development of nitrate tolerance. The aim of this study was to analyse the underlying mechanism by which ramipril, an ACE inhibitor and rosuvastatin, a new molecule of the statin class, are able to protect against the development of nitrate tolerance in the aortas isolated from rats, wild-type (wt) and eNOS-/- mice. <p>These results show that ramipril as well as rosuvastatin are able to protect against the development of nitrate tolerance in the wt and eNOS-/- mice aortas suggesting that eNOS is not necessary for their protective effect. The aortas from nitrate tolerant rats and mice showed a significant increase in the NAD(P)H oxidase activation compared to the aortas from the control and from the co-treated ramipril+NTG or rosuvastatin+NTG animals. In line with these findings were the results obtained by RT-PCR analysis: the mRNA expression of the different subunits of the NAD(P)H oxidase, such as gp91phox, p22phox, were significantly decreased after rosuvastatin or ramipril treatment in wt and eNOS-/- mice aortas. Apocynin, the NAD(P)H oxidase inhibitor was also able to inhibit the development of nitrate tolerance in the rat and mouse aortas. <p>In conclusion, these results suggest that rosuvastatin and ramipril are able to protect against the development of nitrate tolerance by counteracting the nitrate-induced oxidative stress. The mechanism of protection involves a direct interaction with the NAD(P)H oxidase pathway and seems to be completely independent of the eNOS pathway. <p> / Doctorat en sciences pharmaceutiques / info:eu-repo/semantics/nonPublished