Levy A, Yagil Y, Bursztyn M, Barkalifa R, Scharf S, Yagil C. ACE2 expression and activity are enhanced during pregnancy. Am J Physiol Regul Integr Comp Physiol 295: R1953-R1961, 2008. First published October 22, 2008 doi:10.1152/ajpregu.90592.2008.-In the current study, we investigated the expression and activity of ACE2 during pregnancy in normotensive and hypertensive rats, focusing on the relative contribution of the uterus and the placentas, the kidney serving as a reference. We used the Sabra rat model of salt-sensitive hypertension. We confirmed a systemic vasodilatory state during the third trimester of pregnancy, as evidenced by a reduction in blood pressure, both in normotensive and hypertensive rats. At the time that blood pressure was reduced, ACE2 was expressed abundantly in the reproductive organs. The relative levels of ACE2 mRNA in the pregnant animal were placenta Ͼ kidneys Ն uterus and of ACE2 activity kidney Ͼ placenta Ͼ uterus. In the uterus and the placenta, ACE2 expression was unaffected by strain, salt-loading, or the level of blood pressure. ACE2 activity in the uterus of the nonpregnant rat was not affected by any of these variables either, but during pregnancy increased in salt-loaded animals. When estimating the total contribution of the uterus to ACE2 mRNA and activity during pregnancy, we found that the amount of ACE2 mRNA increased in both strains irrespective of diet, but that ACE2 activity increased only in saltloaded animals. We further estimated the relative total contribution of the uterus, placentas, and kidneys to ACE2 expression and activity during pregnancy by adjusting for mass and number of organs and found that the placentas were the major contributors, followed by the kidney and the uterus. We conclude that during pregnancy, the placentas, in particular, but also the uterus, constitute important sources of ACE2, in addition to its normal production in the kidney, leading to an estimated twofold increase in total ACE2 activity. These data are consistent the hypothesis that transient ACE2 overexpression and increased activity during pregnancy may be important in modulating systemic, as well as local hemodynamics in the uteroplacental unit.uterus; placenta; activity THE RENIN-ANGIOTENSIN SYSTEM has long been recognized as a critical regulator of blood pressure control in the mammalian organism. ACE2 is a new component of the renin-angiotensin system that has recently been identified (7). Unlike ACE, ACE2 functions as a carboxy-monopeptidase that cleaves a single residue from ANG I, generating ANG 1-9 and a single residue from ANG II to generate ANG 1-7 (32). ANG 1-7 is a biologically active peptide that has vasodilatory properties that counteract the constrictive effect of ANG II (8, 10). ACE2 is thought to modulate, thereby, the effect of the renin-angiotensin system on vascular tone, in parallel to the modulating effect of ACE (9, 25, 36). Our current knowledge of the physiological and pathological significance of ACE2 is incomplete, although it already appears very lik...

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