Involvement of metalloproteinase and nitric oxide synthase/nitric oxide mechanisms in early decidual angiogenesis-vascularization of normal and experimental pathological mouse placenta related to maternal alcohol exposure

Abstract

Successful pregnancy for optimal fetal growth requires adequate early angiogenesis and remodeling of decidual spiral arterioles during placentation. Prior to the initiation of invasion and endothelial replacement by trophoblasts, interactions between decidual stromal cells and maternal leukocytes, such as uterine natural killer cells and macrophages, play crucial roles in the processes of early maternal vascularization, such as proliferation, apoptosis, migration, differentiation, and matrix and vessel remodeling. These placental angiogenic events are highly dependent on the coordination of several mechanisms at the early maternal-fetal interface, and one of them is the expression and activity of matrix metalloproteinases (MMPs) and endothelial nitric oxide synthases (NOSs). Inadequate balances of MMPs and nitric oxide (NO) are involved in several placentopathies and pregnancy complications. Since alcohol consumption during gestation can affect fetal growth associated with abnormal placental development, recently, we showed, in a mouse model, that perigestational alcohol consumption up to organogenesis induces fetal malformations related to deficient growth and vascular morphogenesis of the placenta at term. In this review, we summarize the current knowledge of the early processes of maternal vascularization that lead to the formation of the definitive placenta and the roles of angiogenic MMP and NOS/NO mechanisms during normal and altered early gestation in mice. Then, we propose hypothetical defective decidual cellular and MMP and NOS/NO mechanisms involved in abnormal decidual vascularization induced by perigestational alcohol consumption in an experimental mouse model. This review highlights the important roles of decidual cells and their MMP and NOS balances in the physiological and pathophysiological early maternal angiogenesis-vascularization during placentation in mice.

Keywords: MMPs; NO; alcohol consumption; maternal angiogenesis; mouse; placental vascularization.

FIGURE 1

Diagrams of early decidual vascularization in the mouse implantation site. In the mouse implantation site (IS) of GD 7, the mesometrial uterine artery (Ua) crosses the myometrium (My), reaches the endometrium (End), and branches in maternal arterioles (ma) in the distal mesometrial decidua (dMD), where few uNKs and macrophages can be found (A). At GD 8–8.5, angiogenesis-remodeling leads to increase in the lumen of decidual SAs (arrow) at the lateral sides of mesometrial decidua with respect to the center of the uterine lumen (UL) and ectoplacental cone (EPC). uNKs and macrophages increase in number in MD (B). By GD 10–11.5, ramified, dilated, and partially remodeled SAs, seen at lateral regions of the proximal mesometrial decidua (pMD), converge at the JZ, forming sinusoidal maternal lacunae that will have contact with the Lab. At this stage, peak uNKs are observed in the pMD. The decidual SA-angiogenesis and remodeling involve several steps (numbered inserts in the upper diagrams of ISs are shown in the bottom panels). The unremodeled SAs are characterized by an intact typical wall with pericytes and VSMCs and ECs [A, step (1)]. In dMD, uNKs and macrophages begin to secrete angiogenic factors around the SAs, inducing maternal vessel destabilization and leading to the separation of VSMCs and pericytes, basement membrane rupture, permeability, ECM remodeling, and disruption of CE junctions [B, step (2)]. At the pMD, sprouting angiogenic events consist of EC migration and proliferation, VSMC remodeling, increased permeability, and maternal blood extravasation [B, step (3)]. At GD10–11.5 (C), tubulogenesis in the pMD involves EC recruitment, EC adhesion and fusion, basement membrane formation, ECM remodeling, and SA elongation and ramification, yielding to vessels with large luminal extensions at the lateral side of IS [C, step (4)]. The SAs arrive at the JZ partially remodeled (without or with few VSMCs), where invasive JZ trophoblasts, derived from spongiotrophoblast (spg), cause apoptosis of maternal EC to eventually replace the maternal endothelium and to form a pseudo-endothelium lined by trophoblastic cells. Trophoblasts, uNKs, and macrophages establish a crosstalk that plays a role via the expression of VEGF, MMPs, NOS, and other factors, in the definitive SA remodeling in the placenta (AMD: antimesometrial decidua).

FIGURE 2

Hypothetical mechanisms of early maternal vascular disruption and altered MMP–NO pathways induced by perigestational alcohol consumption in an experimental mouse model. After PAC, alcohol directly impacts decidual tissue and maternal vasculature, producing OS (1), by which uNKs are diminished (2). In consequence, uNK–VEGF production is also reduced (3). Alcohol and OS induce low KDR expression and KDR activation (phosphorylated pKDR), which conduces to eNOS activation in endothelial cells (CE) and decidual cells (4), producing high levels of NO that enhances OS (5). Thus, bioavailability of NO is reduced in maternal vasculature (6) after PAC, perhaps leading to reduced proliferation and angiogenesis and decidual artery vasoconstriction. PAC-induced OS can be involved in macrophage phenotype change, increasing the inflammatory ratio M1/M2 (7) disrupting the expression (exp) and activity of MMPs (8). In parallel, alcohol and OS may induce increase of lymphocytes (8), which release high levels of proinflammatory cytokines (9) that enhance the balance of M1/M2macrophages in the decidua (7). Proinflamatory macrophages may activate iNOS (10) yielding to increase NO (11). High NO enhances OS and apoptosis in maternal vasculature. Altered macrophagic MMPs and NO contribute to abnormal ECM and CE remodeling, leading to defective decidual vascularization. While there are not differences between normal and abnormal decidual vasculature in non-decidualized endometrium (A, B), in the distal mesometrial decidua (dMD), the abnormal vasculature (D), associated to PAC, consist on maternal vessels with uncompleted remodelled vascular smooth muscle (VSM) cells in the vascular wall (black arrows) and less numbers of endothelial cells (EC), compared to the normal maternal vessel (C) in control condition. Then, in proximal mesometrial decidua (pMD), abnormal maternal vessels exposed to PAC have unremodelled VSM (arrows), disrupted endothelium and increased free EC apoptosis into the lumen, and reduced maternal vascular expansion (F) compared to normal pMD-vasculature (E) which spiral arteries are completely remodelled, expanded and ramified. Overall, disrupted SA angiogenesis in early decidua may result in insufficient maternal artery transformation and subsequent abnormal trophoblast-endothelial replacement and later altered placenta (12).