**Role of the Renin-Angiotensin System in Healthy and Pathological Pregnancies**

Émilie Pepin, Shahin Shabanipour Dehboneh, Nozha Raguema, Maedeh Talebi Esfandarani and Julie L. Lavoie

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66748

### **Abstract**

*Introduction*: Pregnancy is a physiological process that necessitates many cardiovascular and hemodynamic adaptations to ensure the survival of the foetus and well‐being of the mother. The renin‐angiotensin system (RAS) has been suggested as key player in many of these changes as it is critical for blood pressure control as well as fluid and salt homeo‐ stasis in the non‐pregnant state.

*Body*: Normal pregnancy is characterized by an increase in the circulating levels of pro‐ renin, renin, angiotensinogen and angiotensin‐II. However, this is coupled to a dimin‐ ished endothelial sensitivity to angiotensin‐II, which may explain the lack of increase in blood pressure in pregnancy. Conversely, an increase in circulating levels of aldosterone and anti‐diuretic hormone during pregnancy can be observed and could contribute to the enhanced renal sodium and water reabsorption, respectively. Moreover, dysregulation of the RAS has been implicated in the development of gestational hypertensive disorders such as preeclampsia.

*Conclusion*: The difference in the RAS effects observed during normal pregnancy may be attributable to local modifications of the RAS as well as to non‐classic RAS such as the angiotensin‐(1‐7) axis. These adaptations may be dysregulated during preeclampsia and may contribute to the development of the disease.

**Keywords:** gestation, reproductive system, cardiovascular adaptations to gestation, preeclampsia, exercise training

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Menstrual cycle, implantation and pregnancy**

The female reproductive system includes the ovaries, fallopian tubes, uterus, cervix and vagina. It is involved in the production and transportation of gametes, the production of sex hormones and development of embryo. The oviducts extend from the uterus to the ovaries. The egg bursts from the ovary and moves through the oviduct towards the uterus. In humans, an egg lives approxi‐ mately 6–24 hours, unless fertilization occurs, which results in zygote formation. A developing embryo normally reaches the uterus after several days, and then implantation occurs. During implantation, the embryo embeds in the uterine lining, which has been prepared to receive it. The lining of the uterus, called the endometrium, participates in the formation of the placenta, which has a main role in supplying nutrients needed for embryonic and foetal development [1]. At men‐ arche (first menstrual period), females undergo monthly reproductive cycles regulated by the hypothalamus, pituitary gland and ovaries. This so‐called menstrual cycle prepares the reproduc‐ tive system for pregnancy. As shown in **Figure 1**, each menstrual cycle is composed of an ovarian and an uterine cycle based on processes taking place in the ovary and uterus, respectively [1, 2].

**Figure 1.** Human ovarian and menstrual cycles. Diagram of the menstrual cycle (based on several different sources) by Isometrik through Wikimedia Commons licensed under CC BY‐SA 3.0.

The ovarian cycle begins with the menstrual phase from day 1 and lasts, on average, for 5 days. The menstrual phase is followed by the follicular phase, which ends at ovulation at approximately day 14. The third phase is called the luteal phase which lasts from day 14 to 28 and ends with the beginning of menstruations and the start of a new cycle (**Figure 1**) [3]. During the ovarian cycle, there are two hormones released from the anterior pituitary by the stimulatory action of the gonadotropin‐releasing hormone (GnRH): the follicle‐stimulat‐ ing hormone (FSH), which stimulates the development of ovarian follicles and production of estrogen by the follicular cells, and the luteinizing hormone (LH), which serves as the trigger for ovulation and stimulates the follicular cells and corpus luteum to produce progesterone [2]. The cyclic changes in the ovaries with hormonal stimulation of FSH and LH allow follicle maturation and oogenesis, and lead to the release of the secondary oocyte into the oviduct during a process called ovulation (**Figure 1**) [1].

**1. Menstrual cycle, implantation and pregnancy**

84 Renin-Angiotensin System - Past, Present and Future

The female reproductive system includes the ovaries, fallopian tubes, uterus, cervix and vagina. It is involved in the production and transportation of gametes, the production of sex hormones and development of embryo. The oviducts extend from the uterus to the ovaries. The egg bursts from the ovary and moves through the oviduct towards the uterus. In humans, an egg lives approxi‐ mately 6–24 hours, unless fertilization occurs, which results in zygote formation. A developing embryo normally reaches the uterus after several days, and then implantation occurs. During implantation, the embryo embeds in the uterine lining, which has been prepared to receive it. The lining of the uterus, called the endometrium, participates in the formation of the placenta, which has a main role in supplying nutrients needed for embryonic and foetal development [1]. At men‐ arche (first menstrual period), females undergo monthly reproductive cycles regulated by the hypothalamus, pituitary gland and ovaries. This so‐called menstrual cycle prepares the reproduc‐ tive system for pregnancy. As shown in **Figure 1**, each menstrual cycle is composed of an ovarian and an uterine cycle based on processes taking place in the ovary and uterus, respectively [1, 2].

**Figure 1.** Human ovarian and menstrual cycles. Diagram of the menstrual cycle (based on several different sources) by

Isometrik through Wikimedia Commons licensed under CC BY‐SA 3.0.

Estrogen and progesterone produced by the ovarian follicles and corpus luteum during the ovarian cycle cause cyclic changes in the endometrium of the uterus, also known as the uter‐ ine cycle. Both ovarian and uterine cycles last on average 28 days. Menstruation, character‐ ized by the endometrium's breaking down, is the first phase of the uterine cycle and lasts from day 1 to day 5. It also spans part of the follicular phase of the ovarian cycle. Menstruation is followed by the proliferative phase, characterized by estrogen secretion from the primary follicles and lasts for almost 9 days. This phase, which coincides with the growth of the ovar‐ ian follicles in the ovarian cycle, leads to increasing thickness of the endometrium. At the very end of the proliferative phase on day 14, the ovulation occurs. After that, the uterine secretory phase begins. This phase lasts for 13 days and coincides with the formation, function and growth of the corpus luteum in the ovarian cycle [1, 2]. During days 15–28, increased produc‐ tion of progesterone by the corpus luteum in the ovary causes the endometrium of the uterus to double or triple in thickness [1]. This phenomenon prepares the endometrium for receiving the developing embryo in the short period of receptivity known as the window of implanta‐ tion [4]. If fertilization does not occur, the corpus luteum degenerates and the concomitant decrease in progesterone level causes timely destruction of the fully developed endometrium, leading to menstruation. However, if fertilization occurs, the zygote cleavage (increase in cell number without increase in mass) takes place. Following blastocyst formation, the embryo implantation occurs, typically on the sixth day of the luteal phase. This leads to the secretion of the human chorionic gonadotropin (hCG) by the syncytiotrophoblasts of the developing placenta, which acts on the ovaries to maintain the secretion of estrogen and progesterone and prevent the degradation of the corpus luteum. As a result, the luteal phase is prolonged, which prevents the start of the menstrual cycle, and the endometrium continues to grow and undergoes further morphological and molecular changes to provide sufficient support for the growing embryo during the pregnancy [2].

Although it was once thought to be a systemic entity, the presence of local tissue‐specific renin‐angiotensin systems (RASs) has been recently demonstrated. Indeed, different tissues have been found to express all the functional components of the RAS [5, 6]. The reproductive system and placental RAS play a key role in ovulation, implantation, placentation and devel‐ opment of the uteroplacental and umbilicoplacental circulations [7]. Additionally, this local RAS contributes to the activity of circulating maternal renin‐angiotensin‐aldosterone system (RAAS), and as such, influences maternal cardiovascular and renal function [8]. Moreover, the reproductive system RAS has been shown to be implicated in different aspects of repro‐ duction, from fertility to embryo implantation and later through pregnancy [9, 10]. Important modulations of the RAS are observed from the very beginning of pregnancy and aberrant changes in RAS component expression can cause gestational problems such as preeclampsia [11–13]. The implication of the RAS in both normal and pathological pregnancy will be dis‐ cussed in this book chapter.
