Distribution of Angiotensin-(1-7) and ACE2 in Human Placentas of Normal and Pathological Pregnancies
Introduction
Pregnancy is a physiological condition characterized by a paradox between a progressive increase of the different components of the renin–angiotensin system (RAS) and the maintenance of normotension. Findings from Valdés et al. and Brosnihan and collaborators [1], [2], [3], [4] regarding an increased expression of the vasodilator heptapeptide angiotensin-(1-7) [Ang-(1-7)] and the newly cloned angiotensin converting enzyme (ACE) homologue ACE2 have provided novel insights into how the RAS may contribute to the physiological control of blood pressure in this condition.
ACE2 is a carboxypeptidase that exhibits high catalytic efficiency to generate Ang-(1-7) while inactivating Ang II. This catalytic efficiency is almost 500-fold greater than that for converting Ang I to Ang-(1-9) [5], which can then subsequently be converted to Ang-(1-7) by neprilysin and ACE. Thus, ACE2 not only participates in the formation of Ang-(1-7) at the expense of Ang II, but provides an alternate pathway for the formation of Ang-(1-7) [6], [7]. Figure 1 depicts a summary of the components of the RAS illustrating the traditional vasoconstrictive and the novel vasodilatory pathways.
Ang-(1-7) balances the cardiovascular actions of Ang II by modulating vascular tone [8]. The vasodilatory actions of Ang-(1-7) have been reported for a number of vascular beds [9], [10], [11], [12], [13], [14], [15] and involve the release of nitric oxide (NO), kinins, and prostacylins and the potentiation of kinins [9], [10], [11], [12], [16], [17]. Prominent antihypertensive effects of Ang-(1-7) have been demonstrated in experimental hypertensive models [18], [19]. Ang-(1-7) also modulates blood vessel growth and angiogenesis. Ang-(1-7) has been shown to inhibit angiogenesis, opposing the angiogenic actions of Ang II [20], [21]. The antiangiogenic effect of Ang-(1-7), which involves the release of NO, was reversed by the specific Ang-(1-7) antagonist, d-Ala7-Ang-(1-7), but not by traditional AT1 and AT2 receptor antagonists [20].
Recent studies have demonstrated that pregnancy may be a condition of overexpression of Ang-(1-7). In the third trimester of human pregnancy, plasma Ang-(1-7) increased by 34% [3]. A consideration of its functional importance was suggested by the reduction of plasma Ang-(1-7) in preeclampsia, a finding suggesting that the reduction of this peptide may contribute to the elevation of blood pressure [3]. The urinary excretion of Ang-(1-7) and Ang II during singleton, normotensive pregnancies showed a progressive rise throughout normal human gestation, attaining levels 16- and 25-fold higher than that during menstrual cycle, respectively [1]. At 35 weeks of gestation, urinary Ang-(1-7) was the predominant angiotensin peptide in the urine, reaching levels 6-fold higher than Ang II. Studies in experimental pregnant animals confirmed and extended the observations in the human studies by demonstrating an increased renal expression of Ang-(1-7) and ACE2, associated with a 60% increase in urinary excretion of Ang-(1-7) in late pregnancy [2], [4]. In addition, Ang-(1-7) was shown to enhance vasodilation in mesenteric resistance vessels of pregnant rats [2].
With the hypothesis that Ang-(1-7) and ACE2 also contribute to the vasodilatory repertoire of the uteroplacental unit, which up to now has been composed of nitric oxide, prostacyclin and the kallikrein–kinin system, the expression of Ang-(1-7) and ACE2 was evaluated in uteroplacental samples obtained from first trimester spontaneous abortions and ectopic pregnancies and third trimester samples of normal and preeclamptic gestation.
Section snippets
Material and methods
The study protocol, approved by the Institutional Review Board, was conducted at the Hospital Clínico, Pontificia Universidad Católica de Chile. Placentas were obtained from women who had given their informed consent. Tissues were obtained from patients who presented isolated spontaneous abortions or ectopic pregnancies; from normotensive women who gave birth to healthy infants with adequate weight for gestational age and had no miscarriages or preeclamptic pregnancies previous to the index
Results
In the placental villi, the main sites of expression of Ang-(1-7) were the syncytiotrophoblast, cytotrophoblast, the endothelium of the blood vessels (Figure 2A, C, E), and the vascular smooth muscle of the primary and secondary villi (not shown). No differences in expression of the peptide were observed between samples obtained from spontaneous abortions and ectopic pregnancies, so both types of samples were grouped together. In the syncytium, Ang-(1-7) expression is increased in placental
Discussion
This is the first evidence that Ang-(1-7) and its generating enzyme ACE2 are found in different cell types of the human placenta, including the syncytiotrophoblast, villous cytotrophoblasts, invasive and intravascular trophoblast, decidual cells, smooth vascular muscle of primary villi, and in arterial and venous umbilical endothelium.
The syncitial localization of Ang-(1-7) and ACE2 in floating villi supports the idea that the Ang-(1-7) could be secreted into the intervillous space, where it
Acknowledgments
This work was supported in part by grants from the Fondecyt 1020705, NIH/NHLBI (HL51952), NIH/NCHD (HD42631) and NIH/NHLBI (HL67363).
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