Insulin-regulated aminopeptidase deficiency impairs cardiovascular adaptations and placental development during pregnancy

Abstract

Insulin-regulated aminopeptidase (IRAP), an enzyme that cleaves vasoactive peptides including oxytocin and vasopressin, is suggested to play a role in pregnancy and the onset of preeclampsia. Our aim was to examine the contribution of IRAP to arterial pressure regulation and placental development during pregnancy in mice. Mean arterial pressure and heart rate were measured via radiotelemetry in 12-week-old female wildtype and IRAP knockout mice. Females were time-mated with males of the same genotype. Placentae were collected at embryonic day 18.5 for histological analysis. Basal heart rate was ~40 bpm lower in IRAP knockout females compared to wildtype females. The increase in heart rate across gestation was greater in IRAP knockout females than wildtype females. Neither basal nor gestational mean arterial pressure was different between wildtype and IRAP knockout females. Urine output and water intake of IRAP knockout mice were ~45% less than wildtype mice at late gestation. IRAP deficiency had no effect on fetal weight. Morphological assessment of placentae revealed that IRAP deficiency was associated with reduced labyrinth surface area and accumulation of glycogen in the junctional zone. Our data demonstrates that IRAP deficiency alters maternal fluid handling and impairs placental labyrinth expansion at late gestation, indicating that IRAP contributes to the normal adaptions to pregnancy

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

“…Ang IV may have effects on the renal vasculature and renal blood flow that are biphasic with the vasoconstrictor and pressor responses being mediated through AT 1 R while the prolonged vasodilator activity being through IRAP [ 99 ]. IRAP knockout mice do not have altered blood pressure, but do have increased vasopressin sensitivity during pregnancy [ 53 ]. However, we have reported that Ang III increases renal sodium excretion by inhibiting luminal NHE3 and basolateral Na + /K + -ATPase activity in Wistar-Kyoto but not spontaneously hypertensive rats [ 96 ].…”

“…By contrast, nanomolar concentrations of Ang IV have been reported to increase BP in rats by interacting with the AT 1 R [ 48 ]. Some effects of Ang IV in the kidney may be through the binding and inhibition of insulin-regulated aminopeptidase (IRAP) activity [ 52 ]; global IRAP knockout mice have increased vasopressin sensitivity, yet no change in blood pressure [ 53 ].…”

The emerging multifunctional roles of ERAP1, ERAP2 and IRAP between antigen processing and renin-angiotensin system modulation

“…The AT4R is highly expressed in the heart, skeletal muscles, kidneys, small intestine, placenta and blood vessels and alternative splicings result in multiple transcript variants encoding different isoforms. Interestingly, placental AT4R is upregulated during early pregnancy implicating its role in the migration of extravillous trophoblasts (EVT) ( 55 ).…”