The combined role that dNK cells and EVT play in SA remodelling suggests that these interactions could be described as a partnership. The investigation of pregnancy as a multicellular system involving both fetal and maternal components, as well as comparisons to similar examples of tissue remodelling, will further identify the key mechanisms in SA remodelling that are required for a successful pregnancy.

In human pregnancy, successful placentation and remodelling of the uterine vasculature require the integration of a number of stages, which are crucial for a healthy pregnancy. As the demands of the developing fetus for nutrients and oxygen increase, the capacity of the maternal blood vessels to supply this must be altered radically, with deficiencies in this process implicated in a number of dangerous pregnancy complications. The complex signalling networks that regulate these tightly co-ordinated events are becoming clearer as more studies of early pregnancy are performed. It is the aim of this review to draw together our knowledge of events that occur to facilitate a successful pregnancy ranging from the preparation for implantation, through the invasion and differentiation of the trophoblast and the regulation of these processes by other cells within the decidual environment, to the active role that the trophoblast and maternal immune cells play in facilitating the remodelling of the uterine spiral arteries. The events involved in a healthy pregnancy will then be compared to aberrant placentation and remodelling, which are characteristics of many pregnancy disorders, and recent advances in detection of abnormal placental development will also be discussed.

HLA-G is a major histocompatibility complex class Ib molecule whose constitutive tissue distribution is restricted mainly to trophoblast cells at the maternal-fetal interface during pregnancy. In this study, we demonstrated the ability of the soluble HLA-G1 (sHLA-G1) isoform to inhibit fibroblast growth factor-2 (FGF2)-induced capillary-like tubule formation. Using a rabbit corneal neovascularization model, we further showed that sHLA-G1 inhibits FGF2-induced angiogenesis in vivo. We also demonstrated that sHLA-G1 induces endothelial cell apoptosis through binding to BY55/ CD160, a glycosylphosphatidylinositolanchored receptor expressed by endothelial cells. Furthermore, we showed that the specific CL1-R2 anti-CD160 monoclonal antibody mimics sHLA-G1-mediated inhibition of endothelial cell tube formation and induction of apoptosis. Thus, the engagement of CD160 in endothelial cells may be essential for the inhibition of angiogenesis. sHLA-G1/CD160-mediated antiangiogenic property may participate in the vascular remodeling of maternal spiral arteries during pregnancy, and, given that we found that CD160 is strongly expressed in the vasculature of a murine tumor, it offers an attractive therapeutic target for preventing pathologic neovascularization. ( IntroductionHLA-G is a human major histocompatibility complex (MHC) class Ib gene characterized by a unique promoter region, limited polymorphism, restricted constitutive tissue distribution, and several spliced transcripts encoding either membrane-bound or soluble proteins. 1 The soluble HLA-G1 (sHLA-G1) isoform derives from mRNA retaining intron 4, 2 which contains a stop codon that precludes translation of the transmembrane domain. Such intron 4 retention is unique among all HLA class I molecules described to date. This 37-kDa, intron 4-retaining sHLA-G1 isoform associates noncovalently with ␤2-microglobulin (␤2m). 2 Soluble HLA-G can also be generated by metalloproteinase-mediated release of surface HLA-G containing only extracellular domains. 3 The predominant expression of sHLA-G1 in the placenta, at a time when polymorphic HLA-A and HLA-B class Ia molecules are repressed, is consistent with important immunologic functions during pregnancy. 4 sHLA-G1 induces apoptosis of activated CD8 ϩ T and natural killer (NK) cells 5,6 and down-regulates the CD4 ϩ T-cell alloproliferation response. 7 The observation that some anti-HLA-G monoclonal antibodies bound to HLA-G-negative placental endothelial cells 8,9 led to our hypothesis that sHLA-G1 might bind to these cells and be involved in the modulation of placental angiogenesis or uterine vessel remodeling. 8 Several further observations are in line with such a novel function of HLA-G. Among them is that a defect of HLA-G expression in extravillous cytotrophoblast is associated with preeclampsia, 10,11 a common complication of pregnancy in which HLA-G ϩ endovascular trophoblast invasion of maternal spiral arteries is abrogated, compromising blood flow to the maternal interface. 12 In addition, it has been shown that HL...

A number of important changes take place in the maternal uterine vasculature during the first few weeks of pregnancy resulting in increased blood flow to the intervillous space. Vascular endothelial and smooth muscle cells are lost from the spiral arteries and are replaced by fetal trophoblast cells. Failure of the vessels to remodel sufficiently is a common feature of pregnancy pathologies such as early pregnancy loss, intrauterine growth restriction and pre-eclampsia. There is evidence to suggest that some vascular changes occur prior to trophoblast invasion, however, in the absence of trophoblasts remodelling of the spiral arteries is reduced. Until recently our knowledge of these events has been obtained from immunohistochemical studies which, although extremely useful, can give little insight into the mechanisms involved. With the development of more complex in vitro models a picture of events at a cellular and molecular level is beginning to emerge, although some caution is required in extrapolating to the in vivo situation. Trophoblasts synthesise and release a plethora of cytokines and growth factors including members of the tumour necrosis factor family. Studies suggest that these factors may be important in regulating the remodelling process by inducing both endothelial and vascular smooth muscle cell apoptosis. In addition, it is evident from studies in other vascular beds that the structure of the vessel is influenced by factors such as flow, changes in the composition of the extracellular matrix, the phenotype of the vascular cells and the local immune cell environment. It is the aim of this review to present our current knowledge of the mechanisms involved in spiral artery remodelling and explore other possible pathways and cellular interactions that may be involved, informed by studies in the cardiovascular field.

Objective-Invasion of uterine spiral arteries by extravillous trophoblasts in the first trimester of pregnancy results in loss of endothelial and musculoelastic layers. This remodeling is crucial for an adequate blood supply to the fetus with a failure to remodel implicated in the etiology of the hypertensive disorder preeclampsia. The mechanism by which trophoblasts induce this key process is unknown. This study gives the first insights into the potential mechanisms involved. Methods and Results-Spiral arteries were dissected from nonplacental bed biopsies obtained at Caesarean section, and a novel model was used to mimic in vivo events. Arteries were cultured with trophoblasts in the lumen, and apoptotic changes in the endothelial layer were detected after 20 hours, leading to loss of endothelium by 96 hours. In vitro, coculture experiments showed that trophoblasts stimulated apoptosis of primary decidual endothelial cells and an endothelial cell line. This was blocked by caspase inhibition and NOK2, a FasL blocking antibody. NOK2 also abrogated trophoblast-induced endothelial apoptosis in the vessel model. Key Words: apoptosis Ⅲ endothelium Ⅲ trophoblast Ⅲ pregnancy Ⅲ arteries R emodeling of the uterine arteries is a key event in early pregnancy. In the first trimester of pregnancy, a subpopulation of fetal trophoblast cells, the extravillous trophoblast, invade the uterine wall (interstitial invasion) and its blood vessels (endovascular invasion) as far as the myometrial segments. In the uterine spiral arteries, the trophoblasts interdigitate between the endothelial cells (ECs), replacing the endothelial lining and most of the musculoelastic tissue in the vessel walls. This creates a high-flow, low-resistance circulation that increases maternal blood flow to the placental villi at the maternal-fetal interface. Conclusions-ExtravillousData suggest that trophoblasts bind to and migrate along the luminal surfaces of the endothelium and transiently coexist on the walls of partially modified spiral arteries before replacing the endothelium. 1,2 Little is known as to how these processes are regulated in normal pregnancies; however, their pivotal importance in the establishment and maintenance of a successful pregnancy is illustrated when they fail to occur or occur to a significantly reduced extent. Defective remodeling of the spiral arteries is associated with pregnancies complicated by preeclampsia and intrauterine growth restriction (IUGR) 3 and is proposed to lead to an overall state of oxidative stress or fluctuations in oxygen concentrations analogous to hypoxia-reperfusion within the placental environment. 4 Preeclampsia and IUGR are responsible for considerable perinatal mortality and morbidity and carry health implications in adult life, including increased risk of hypertension, heart disease, and diabetes. 5 The importance of interactions between trophoblasts and the vascular cells of the spiral arteries, which may account for these differences in remodeling, have yet to be determined in normal or compli...