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

妊娠需要许多代谢和心血管变化，以使胎儿健康发育。例如，需要增加血容量以适当地灌注胎盘和胎儿。这被认为主要是由循环血管紧张素II的增加引起的，血管紧张素II刺激醛固酮的产生，从而引起水潴留。相反，妊娠与对血管收缩剂（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维持正常的血压，并表明在特定组织中，肾素-血管紧张素系统与妊娠有差异调节。 事实上，尽管最初认为系统性肾素-血管紧张素系统是非妊娠状态下血压和体液稳态相关调节的主要效应物，但已变得明显的是，许多组织含有肾素-血管紧张素系统的所有组分并且具有重要贡献。此外，很明显，这一系统所涉及的远不止“经典”效应。例如，它已被证明可能参与胎盘发育。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、动脉或肾脏中，以产生与妊娠相关的适当适应。 此外，在过去十年中，该系统增加了新的组成部分，其贡献仍有待于在酝酿期间进行评估。例如，已经表征了肾素-血管紧张素系统的“良好”轴，其中血管紧张素II可以通过血管紧张素转化酶2降解为血管紧张素-（1-7）。然后，所产生的血管紧张素-（1-7）可刺激其自身的受体Mas受体，以产生与血管紧张素II的效应相反的效应，例如血管舒张和抗凋亡效应。因此，在妊娠期间，该轴可能在特定组织（例如血管）中上调，以对抗循环血管紧张素II的增加，尽管关于这一点的信息非常有限。因此，本研究计划的目的是确定在小鼠模型中，妊娠期间肾素-血管紧张素系统的哪些组分是如何以及在哪些组织中被调节的。 方法：我的实验室已经开发出一种专门知识，在妊娠期间的心血管适应的生理学研究在小鼠模型。事实上，小鼠妊娠与人类妊娠有许多相似之处，例如血压变化和胎盘发育，因此是一种选择模型。我的实验室对肾素-血管紧张素系统也非常感兴趣，因此，研究该系统所需的许多工具已经到位。因此，我们将评估许多组织如肾、动脉、肺、肝、子宫和卵巢中的肾素-血管紧张素系统组分（血管紧张素II和血管紧张素-（1-7）轴）的变化。我们将通过比较妊娠不同阶段（妊娠第4、8、14和18天）的未妊娠雌性与妊娠雌性来研究这些成分如何随妊娠而改变。我们将在这些变化和妊娠期间观察到的心血管变化（如通过无线电遥测测量的血压、离体肠系膜动脉中的血管反应性和血容量扩张）之间进行比较。 我们还将评估在胎盘发育的不同阶段，组织学如何调节胎盘中的肾素-血管紧张素系统。 相关性：这些研究将有助于提高我们对不同因素的理解，这些因素有助于与妊娠相关的心血管调节。

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.