Dysregulation of the placental renin–angiotensin system in human fetal growth restriction

Abstract

Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin–angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.

Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age

“…Indeed, ACE2 metabolizes Ang II and reduces its levels and produces the vasodilator peptide, Ang-(1-7). Therefore, it is critical for regulating the actions of Ang II mediated by its AT 1 R. A previous study from our group showed that placental ACE2 mRNA expression was lower in pregnancies associated with fetal growth restriction (Delforce et al, 2019), suggesting that reduced placental ACE2 levels and reduced Ang-(1-7) production might contribute to the etiology of SGA. The elevation in plasma ACE2 levels in SGA, taken together with the reduction in placental ACE2, suggests, however, that placental ACE2 is not contributing to the high levels of sACE2 in the maternal circulation in SGA pregnancies.…”

“…It is activated by estrogen-induced increases in angiotensinogen (AGT) and, subsequently, by the reduction in systemic vascular resistance caused by the ovarian hormone, relaxin (Lumbers and Pringle, 2014). It is perhaps not surprising then that alterations in the circulating and intrauterine RAS are associated with the development of preeclampsia (PE) and pregnancies in which the infant is born small for gestational age (SGA) (Irani and Xia, 2008;Zhou et al, 2013;Delforce et al, 2019).…”

Prevalence of Growth Restriction at Birth for Newborns With Congenital Heart Defects: A Population-Based Prospective Cohort Study EPICARD

“…However, enhanced cerebral perfusion occurs at the expense of fetal liver, renal, pancreatic and mesenteric circulation, which in turn results in decreased production of insulin growth factor, angiotensin and other endocrine hormones essential for fetal growth (22). These hormones may affect the fetal growth directly as is the case of insulin growth factor or indirectly via placental function (e.g., renin-angiotensin system), inducing an inflammatory response or through other biomolecular pathways (23,24).…”

Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019

“…180,181 These drugs modifying the reninangiotensin cascade could also affect placental functions leading to growth retardation. 182 Other drugs with vascular impact Sildenafil, a phosphodiesterase type 5 inhibitor, is a vasodilator used to treat erectile dysfunction and pulmonary arterial hypertension. It is under investigation in patients with COVID-19 (NCT04304313) because pulmonary hypertension is a complication of ARDS.…”