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

怀孕需要许多新陈代谢和心血管变化，以保证胎儿的健康发育。例如，需要增加血容量才能适当地对胎盘和胎儿进行灌流。这被认为主要是由于循环中血管紧张素II的增加，刺激了醛固酮的产生，从而导致了水分保持。相反，妊娠与血管收缩药(如血管紧张素II)的敏感性降低有关。因此，这可能有助于在妊娠期间保持正常的血压，并表明肾素-血管紧张素系统在特定组织中随着妊娠的不同而受到不同的调节。 事实上，尽管最初认为全身性肾素-血管紧张素系统是非妊娠状态下调节血压和体液平衡的主要效应者，但事实证明，许多组织包含肾素-血管紧张素系统的所有成分，并具有重要的贡献。此外，很明显，这一体系牵涉到的远不止“经典”效应。例如，已经证明它可能参与胎盘的发育。因此，在妊娠期间，局部组织的肾素-血管紧张素系统可能受到不同的调节，例如，在胎盘、子宫、动脉或肾脏，以产生与妊娠相关的适当适应。 此外，在过去十年中增加了该系统的新组成部分，这些组成部分的贡献仍有待在酝酿期间进行评估。例如，肾素-血管紧张素系统的“良好”轴已被定性为血管紧张素II可以被血管紧张素转换酶2降解为血管紧张素-(1-7)，然后产生的血管紧张素-(1-7)可以刺激它自己的受体Mas受体，产生与血管紧张素II相反的作用，如血管扩张和抗凋亡作用。因此，有可能在妊娠期间，在特定的组织中，例如在血管中，可能存在这个轴的上调，以对抗循环中血管紧张素II的增加，尽管关于这方面的信息非常有限。因此，该研究计划的目的是确定在小鼠模型中，肾素-血管紧张素系统的哪些成分在怀孕期间是如何以及在哪些组织中被调节的。 方法：我的实验室在研究妊娠期间心血管适应的生理学方面已经在小鼠模型上形成了专业知识。事实上，小鼠的妊娠与人类的妊娠有许多相似之处，例如在血压变化和胎盘发育方面，因此是一种选择的模型。我的实验室对肾素-血管紧张素系统也非常感兴趣，因此，研究这一系统所需的许多工具已经到位。因此，我们将评估肾素-血管紧张素系统的组成部分的变化，包括血管紧张素II和血管紧张素-(1-7)轴，在许多组织中，如肾、动脉、肺、肝、子宫和卵巢。我们将通过比较怀孕不同阶段(怀孕第4天、第8天、第14天和第18天)的未怀孕女性和怀孕女性，来研究这些成分是如何随着怀孕而改变的。我们将把这些变化与妊娠期间观察到的心血管变化进行比较，如无线电遥测血压、离体肠系膜动脉的血管反应性和血容量扩张。我们还将评估肾素-血管紧张素系统如何在胎盘发育的不同阶段通过组织学进行调节。 相关性：这些研究将有助于加强我们对与妊娠相关的心血管调节的不同因素的理解。

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.