Suppression of classical renin-angiotensin system and increase of soluble ACE2 in pregnancies with adverse outcomes

Hypertension during pregnancy increases the risk for adverse maternal and fetal outcomes, but mechanisms of pregnancy hypertension are not precisely understood. Elevated plasma renin activity and aldosterone concentrations play an important role in the normal physiologic adaptation to pregnancy. These effectors are reduced in patients with pregnancy hypertension, creating an opportunity to define features of the renin-angiotensin-aldosterone system (RAAS) that are characteristic of this disorder. In the current study, we used a novel LC-MS/MS-based methodology to develop comprehensive profiles of RAAS peptides and effectors over gestation in a cohort of n=74 pregnant women followed prospectively for the development of gestational hypertension and pre-eclampsia (HYP, n=27) versus remaining normotensive (NT, n=47). In NT pregnancy, the plasma renin activity surrogate, (PRA-S, calculated from the sum of [angiotensin I] + [angiotensin II) and aldosterone concentrations significantly increased from first to third trimester, accompanied by a modest increase in concentrations of angiotensin peptide metabolites. In contrast, in HYP pregnancies PRA-S and angiotensin peptides were largely unchanged over gestation, and third trimester aldosterone concentrations were significantly lower compared to NT pregnancies. Results indicate that the predominate features of pregnancies that develop HYP are stalled or waning activation of the RAAS in the second half of pregnancy (accompanied by unchanging levels of angiotensin peptides) and attenuated secretion of aldosterone.