Abstract
BackgroundIn humans, trophoblast invasion, vascular remodeling and placental development are critical to determine the fate of pregnancy. Since guinea-pigs (GP) and humans share common pregnancy features including extensive trophoblast invasion, transformation of the uterine spiral arteries and a haemomonochorial placenta, the GP animal model was deemed suitable to extend our knowledge on the spatio-temporal immunoreactive expression of the vasodilator arpeptide of the renin-angiotensin system, angiotensin-(1–7) [Ang-(1–7)] and its main generating enzyme, angiotensin converting enzyme 2 (ACE2).MethodsUtero-placental units were collected in days 15, 20, 40 and 60 of a 64–67 day long pregnancy in 25 Pirbright GP. Ang-(1–7) and ACE2 expression in utero-placental units were evaluated by immunohistochemistry.ResultsAng-(1–7) and ACE2 were detected in the endothelium and syncytiotrophoblast of the labyrinthine placenta, interlobium, subplacenta, giant cells, syncytial sprouts, syncytial streamers, and myometrium throughout pregnancy. In late pregnancy, perivascular or intramural trophoblasts in spiral and mesometrial arteries expressed both factors. Immunoreactive Ang-(1–7) and ACE2 were present in decidua and in the vascular smooth muscle of spiral, myometrial and mesometrial arteries, which also express kallikrein (Kal), the bradykinin receptor 2 (B2R), vascular endothelial growth factor (VEGF) and its type 2 receptor (KDR), but no endothelial nitric oxide synthase (eNOS). In addition, the signal of Ang-(1–7) and ACE2 was especially remarkable in giant cells, which also show Kal, B2R. eNOS, VEGF and KDR.ConclusionsThe spatio-temporal expression of Ang-(1–7) and ACE2 in GP, similar to that of humans, supports a relevant evolutionary conserved function of Ang-(1–7) and ACE2 in decidualization, trophoblast invasion, vascular remodeling and placental flow regulation, as well as the validity of the GP model to understand the local adaptations of pregnancy. It also integrates Ang-(1–7) to the utero-placental vasodilatory network. However, its antiangiogenic effect may counterbalance the proangiogenic activity of some of the other vasodilator components.
Highlights
In humans, trophoblast invasion, vascular remodeling and placental development are critical to determine the fate of pregnancy
Ang-(1–7) and angiotensin converting enzyme 2 (ACE2) expression was coarsely granular in giant cells and vascular smooth muscle, finely granular in the labyrinth, interlobium and decidual cells, and diffuse with a peripheral reinforcement in syncytial streamers
The spatio-temporal expression of Ang-(1–7) and ACE2 in sites related to decidualization, trophoblast invasion, vascular remodeling, placental flow regulation and platelet antiaggregation supports a relevant role of these peptides/proteins in the gestation of the guinea-pig
Summary
Trophoblast invasion, vascular remodeling and placental development are critical to determine the fate of pregnancy. Extravillous trophoblasts (EVT) after anchoring in the uterine wall migrate through the decidualized stroma to invade the uterine spiral arteries. This last process destroys vascular smooth muscle and replaces the endothelium with EVT by the second trimester of pregnancy. This remodeling increases vessel diameter and creates a high flow, low resistance arteriolar system that meets the increased. Apart from vasoactive effects, Ang II stimulates proliferation and angiogenesis [8,9], while Ang-(1–7) is antiproliferative and antiangiogenic [10]
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