Mechanisms implicated in the modulation of the renin-angiotensin system during gestation in a mouse model

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Gestation requires many metabolic and cardiovascular changes to allow for the healthy development of the fetus. For instance, an increase in blood volume is required to appropriately perfuse the placenta and fetus. This is thought to be mainly produced by an increase in circulating angiotensin II which stimulates the production of aldosterone and thus, water retention. Conversely, gestation is associated with a decreased sensitivity to vasoconstrictors, such as angiotensin II. As such, this may contribute to maintaining a normal blood pressure during gestation, and suggests that the renin-angiotensin system is differentially modulated with gestation in specific tissues. *Indeed, although it was originally thought that the systemic renin-angiotensin system was the main effector for the associated regulation of blood pressure and fluid homeostasis in non-pregnant state, it has become evident that many tissues contain all the components of the renin-angiotensin system and have important contributions. Moreover, it is also clear that this system is implicated in much more than the "classical" effects. For instance, it has been shown that it may be involved in placental development. Therefore, during gestation, local tissue renin-angiotensin systems may be regulated differentially, for instance, in the placenta, uterus, arteries or kidney, to produce the appropriate adaptations associated with gestation.*In addition, new components of the system have been added in the last decade which contributions remain to be evaluated during gestation. For instance, a "good" axis of the renin-angiotensin system has been characterized where Angiotensin II can be degraded to Angiotensin-(1-7) by the angiotensin-converting enzyme 2. The produced Angiotensin-(1-7) can then stimulate its own receptor, the Mas receptor, to produce effects which are opposite to those of Angiotensin II such as vasodilation and anti-apoptotic effects. Therefore, it is possible that during gestation, there may be an upregulation of this axis in specific tissues, for instance in blood vessels, to counter the increase in circulating Angiotensin II although there is very limited information regarding this. As such, the aim of this research program is to determine how and in what tissues which components of the renin-angiotensin system are modulated during gestation in a mouse model.*Methods: My laboratory has developed an expertise in the study of the physiology of the cardiovascular adaptations during gestation in a mouse model. Indeed, mice gestation has many similarities with human gestation, for instance regarding blood pressure changes and placental development, and is thus a model of choice. My laboratory is also very interested in the renin-angiotensin system and as such, many of the tools required to investigate this system are already in place. We will thus evaluate the changes in components of the renin-angiotensin system, both the Angiotensin II and Angiotensin-(1-7) axis, in many tissues such as the kidney, arteries, lung, liver, uterus and ovaries. We will investigate how these components are modified with gestation by comparing non-pregnant females to pregnant females at different stages of gestation (day 4, 8, 14 and 18 of gestation). We will make a parallel between these changes and cardiovascular modifications observed during gestation such as blood pressure by radiotelemetry, vascular reactivity in isolated mesenteric arteries and blood volume expansion. We will also assess how the renin-angiotensin system is modulated in the placenta by histology at different stages in its development.*Relevance: These studies will help enhance our understanding of the different factors which contribute to the cardiovascular modulations which are associated with gestation.