Human placental renin–angiotensin system in normotensive and pre‐eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult

Abstract

Key pointsr The development of the human placenta occurs in a low oxygen environment which stimulates angiogenesis and vascularization.r Placental expression of the renin angiotensin system (RAS) is highest in early pregnancy.Although both the RAS and oxygen stimulate angiogenesis, it is not known how they interact during placental development.r Pre-eclampsia (PE), a condition characterized by poor placental development and elevated oxidative stress has increased incidence in populations living at high altitude and thus exposed to hypobaric hypoxia.r This study aimed to investigate the effects of various forms of oxidative stress on the placental RAS.r The results suggest that the placental RAS is activated by oxidative insults but the component type and the degree of activation is dependent on the nature of the insult.Abstract A functioning placental renin-angiotensin system (RAS) appears necessary for uncomplicated pregnancy and is present during placentation, which occurs under low oxygen tensions. Placental RAS is increased in pre-eclampsia (PE), characterised by placental dysfunction and elevated oxidative stress. We investigated the effect of high altitude hypoxia on the RAS and hypoxia-inducible factors (HIFs) by measuring mRNA and protein expression in term placentae from normotensive (NT) and PE women who delivered at sea level or above 3100 m, using an explant model of hypoxia-reoxygenation to assess the impact of acute oxidative stress on the RAS and HIFs. Protein levels of prorenin (P = 0.049), prorenin receptor (PRR; P = 0.0004), and angiotensin type 1 receptor (AT1R, P = 0.006) and type 2 receptor (AT2R, P = 0.002) were all significantly higher in placentae from NT women at altitude, despite mRNA expression being unaffected. However, mRNA expression of all RAS components was significantly lower in PE at altitude than at sea level, yet PRR, angiotensinogen (AGT) and AT1R proteins were all increased. The increase in transcript and protein expression of all the HIFs and NADPH oxidase 4 seen in PE compared to NT at sea level was blunted at high altitude. Experimentally induced oxidative stress stimulated AGT mRNA (P = 0.04) and protein (P = 0.025). AT1R (r = 0.77, P < 0.001) and AT2R (r = 0.81, P < 0.001) mRNA both significantly correlated with HIF-1β, whilst AT2R also correlated with HIF-1α (r = 0.512, P < 0.013). Our observations suggest that the placental RAS is responsive to changes in tissue oxygenation: this could be important in the interplay between reactive oxygen species as cell-signalling molecules for angiogenesis and hence placental development and function.

Maternal Exposure to Ambient Air Pollution and Risk of Preeclampsia: A Population-Based Cohort Study in Scania, Sweden

“…Furthermore, the only well-established environmental factor associated with increased incidence of PE to date is living at high altitude [55]. Above 2700 m, an increased expression of the angiotensin type I receptor in the placental renin-angiotensin system causes vasoconstriction and contributes to oxidative stress in the placenta [56,57]. Thus, our study results enhance support for and evidence of ambient air pollution being an additional environmental factor important to the development of preeclampsia.…”

Preeclampsia and the brain: neural control of cardiovascular changes during pregnancy and neurological outcomes of preeclampsia

“…The hallmark placental ischemia observed in PE triggers increased expression of prorenin receptors (PRRs), which promote the generation of angiotensin I from AGT, and the subsequent cleavage of AngII from Ang I by angiotensin converting enzyme (ACE) (119). Morover, the binding of prorennin to PRRs exerts nearly a four-fold increase in the catalytic efficiency of PRR (117, 133). …”

“…The placental RAAS demonstrates high sensitivity to tissue levels of reactive oxygen species (ROS), which serve as a signal for both angiogenesis (116) and placental development (117). Overactivation of the placental RAAS, such as in cases of placental ischemia, results in excess local production of AngII, which acting on AT1Rs expressed by placental trophoblasts (124), can lead to the deleterious effects of low birthweight and intrauterine growth restriction (119).…”

“…The AGT protein maintains a state of equilibrium between its oxidized and reduced forms (130). Excessive ROS production by the ischemic placenta catalyzes a disulfide linkage in the angiotensin portion of AGT, and this oxidized form of AGT results in the four-fold incease in Ang I production (117, 130), subsequent cleavage to AngII, and then enhanced pressor response brought about by the vasoconstrictive properties of AngII (119, 134). Thus, maternally derived AngII produced from the uterine placental bed acts in an endocrine manner to produce vasoconstriction of the uterine spiral arteries, further exacerbating placental ischemia (114, 115).…”

Hypoxia, fetal and neonatal physiology: 100 years on from Sir Joseph Barcroft

“…In placentae obtained from normotensive and pre‐eclamptic women at sea level and at high altitude, Kurlak et al . () report that the placental renin–angiotensin system is responsive to changes in tissue oxygenation. They introduce the concept that this could be important in the interplay between reactive oxygen species as cell‐signalling molecules for angiogenesis and, hence, placental development and function.…”