Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring Cardiovascular Health Across the Life Course: Moving the Field Forward: A Scientific Statement From the American Heart Association

Abstract

There is increasing interest in the long-term cardiovascular health of women with complicated pregnancies and their affected offspring. Emerging antenatal risk factors such as preeclampsia appear to increase the risk of hypertension and cardiovascular disease across the life course in both the offspring and women after pregnancy. However, the antenatal programming mechanisms responsible are complex and incompletely understood, with roots in alterations in the development, structure, and function of the kidney, heart, vasculature, and brain. The renin-angiotensin-aldosterone system is a major regulator of maternal-fetal health through the placental interface, as well as kidney and cardiovascular tissue development and function. Renin-angiotensin-aldosterone system dysregulation plays a critical role in the development of pregnancy complications such as preeclampsia and programming of long-term adverse cardiovascular health in both the mother and the offspring. An improved understanding of antenatal renin-angiotensin-aldosterone system programming is crucial to identify at-risk individuals and to facilitate development of novel therapies to prevent and treat disease across the life course. Given the inherent complexities of the renin-angiotensin-aldosterone system, it is imperative that preclinical and translational research studies adhere to best practices to accurately and rigorously measure components of the renin-angiotensin-aldosterone system. This comprehensive synthesis of preclinical and translational scientific evidence of the mechanistic role of the renin-angiotensin-aldosterone system in antenatal programming of hypertension and cardiovascular disease will help (1) to ensure that future research uses best research practices, (2) to identify pressing needs, and (3) to guide future investigations to maximize potential outcomes. This will facilitate more rapid and efficient translation to clinical care and improve health outcomes.

Activation of the Renin–Angiotensin–Aldosterone System Is Attenuated in Hypertensive Compared with Normotensive Pregnancy

“…New-onset hypertension during pregnancy (gestational hypertension or pre-eclampsia) affects 5–10% of pregnancies, and the prevalence in the United States is rising [ 1 ]. The development of hypertension during pregnancy is associated with long-term health risks for both the mother and the offspring [ 2 ], and increases the maternal risk of cardiovascular diseases later in life [ 3 , 4 ]. Knowledge of the mechanisms underlying perinatal hypertension could lead to improved strategies for the treatment and/or management of hypertension during pregnancy [ 5 , 6 ].…”

The Renin–Angiotensin System and Cardiovascular–Kidney–Metabolic Syndrome: Focus on Early-Life Programming

“…Conversely, reduced levels of angiotensin-(1-7) in pregnant women have been observed in conditions like preeclampsia [ 88 ], preterm birth [ 89 ], and gestational diabetes [ 90 ]. Consequently, these RAS components may instigate secondary alterations in the neurohormonal regulation of cardiovascular and kidney function, potentially programming hypertension, kidney disease, and cardiovascular disease (CVD) [ 91 ]. Nevertheless, the specific timing of these RAS changes and their significance in the later development of CKM syndrome remain largely unclear.…”

Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus

“…Indeed, evidence points to a close connection between miR-21 and organ damage associated with hypertension ( 105 ). Moreover, miR-27a and miR-27b have been linked to the downregulation of ACE1 gene expression, while reduced levels of miR-330 can upregulate angiotensin II type-2 (AT2) receptor gene translation, thereby affecting the RAAS pathway in the fetal brain under malnourished conditions ( 106 ) ( Table 4 ).…”