Rôle de l'angiotensine-(1-7), peptide contre-régulateur de l'angiotensine II, dans la programmation développementale de l'hypertension artérielle et de la fonction cardiaque.
It has been proposed that perinatal and early postnatal life can result in the programming of adult diseases. However, the mechanisms that elicit such alterations are not fully understood. Oxidative stress generated in different models of programming, through exposure to dietary manipulation or neonatal exposure to hyperoxic stress, appears as an important mechanism affecting adult cardiovascular function.
Recently, it has been demonstrated in rats that neonatal O2 exposure leads to hypertension, vascular dysfunction and extracellular matrix changes later in life. Importantly, vascular structural changes and microvascular rarefaction precede elevation of blood pressure. However, it remains to be determined whether cardiac dysfunction and oxidative stress, changes in cardiac structure and fibrosis also prevail in these hypertensive animals.
The classical axis of the renin-angiotensin system (RAS), ACE/Ang II/AT1 receptor, plays an important role in the establishment and maintenance of elevated blood pressure in neonatal and other models of developmental programming of hypertension. The new RAS axis, ACE2-Ang(1-7)-Mas receptor, is beginning to be viewed as the principal counter-regulatory mechanism for the classical AT1-mediated effects of Ang II. In this project, we hypothesize that an imbalance between AngII/Ang(1-7) production participates in the vascular and – postulated – cardiac dysfunction and enhanced oxidative stress associated with neonatal hyperoxic exposure.
The proposed research should shed light on the mechanisms underlying major health issues: the impact of O2-related damage of prematurity on cardiovascular risks and the overall concept of developmental programming of hypertension and cardiac diseases. Many studies now indicate that prematurity is associated with vascular dysfunction and high blood pressure in childhood, but the impact of perinatal conditions on heart development and function is not well known in either experimental animal models or humans. Considering that 8% of the population is born prematurely and that survival has increased markedly over the last three decades, these studies are particularly relevant to the growing proportion of adults born prematurely and possibly at significant risk of cardiovascular diseases.