Pregnancy provides an opportunity to reveal various cardiovascular disease risk factors and estimate a woman's lifetime risk because of its unique cardiovascular and metabolic stress. Pulsed Doppler ultrasonography in the uterine artery may be useful in distinguishing women with recurrent pregnancy loss (RPL) caused by vascular dysfunction from women with unexplained RPL. Furthermore, the plasma level of adrenomedullin, which is often associated with pathological processes of the vasculature, is elevated in women with RPL. In the light of these studies, vascular dysfunction may be the key to the pathophysiology of pregnancy loss.

History of pregnancy loss is known to be associated with a higher risk of myocardial infarction, and the risk increased significantly with the number of pregnancy loss. Reproductive history of obstetrical complications associated with RPL such as preeclampsia, premature delivery, fetal growth restriction, and placental abruption could be considered a“failed stress test,” possibly unmasking early or preexisting vascular dysfunction and vascular or metabolic disease. Therefore, these women should be carefully monitored and controlled. Healthcare professionals should take a careful and detailed history of RPL and characteristic pregnancy complications.

It is unlikely to treat all young women with low dose aspirin following the occurrence of PRL without any other risk factors. Pharmacological therapies for hypertension, insulin resistance, or dyslipidemia are also available but should be tailored on an individual basis.

Autophagy is an evolutionarily conserved process in eukaryotes, by which cytoplasmic cargo sequestered inside double-membrane vesicles are delivered to the lysosome for degradation. In early pregnancy, trophoblasts and the fetus experience hypoxic and low-nutrient conditions; nevertheless, extravillous trophoblasts (EVTs) invade the uterine myometrium up to one third of its depth and migrate along the lumina of spiral arterioles, replacing the maternal endothelial lining. An enhancement of autophagy induced by physiological hypoxia takes part in the invasion and vascular remodeling in EVTs. On the other hand, soluble endoglin, which increased in sera in preeclamptic cases, suppressed EVT-invasion or -vascular remodeling by inhibiting autophagy in vitro. In addition, a substance selectively degraded by autophagy, p62/SQSTM1, accumulated in EVT cells in preeclamptic placental bed biopsy samples showing impaired autophagy in vivo. There is, however, still a conflict in state of autophagy in preeclamptic placentas. In this paper, we review the importance of autophagy inhibition for placentation, and propose the future direction of autophagy in placenta.

<Objectives>

Adenosine (Ado) is a signaling molecule known to be induced by hypoxia and to be involved in the pathophysiology of various disease. We recently reported that Ado levels and the enzymatic activity of CD73, an enzyme that converts AMP to Ado, are elevated in preeclampsia (PE) patient placentas. However, pathophysiological role of placental CD73 in PE remains unknown. Here, we assessed the function of CD73 and the significance of Ado signaling in vivo by using angiotensin II type 1 receptor agonistic autoantibody (AT₁-AA)-induced PE mouse model.

<Methods>

PE mouse model induced by AT₁-AA isolated from PE patient sera was conducted. AT₁-AA-induced phenotypes of wild type (WT), CD73-deficient (Cd73^-/-), and A2B Ado receptor (ADORA2B) -deficient (Adora2b^-/-) dams were examined. The research protocol was approved by our institution and informed consent was obtained from all patients.

<Results>

Placental Ado levels and CD73 expression were significantly induced in AT₁-AA-treated WT dams. We found that placental Ado levels were significantly reduced in AT₁-AA-treated Cd73^-/- dams compared with WT dams. Additionally, AT₁-AA-induced PE features, hypertension and proteinuria, were attenuated in Cd73^-/- dams compared with WT dams. Expression analysis of Ado receptors revealed that only ADORA2B expression was significantly elevated in the placenta of AT₁-AA-treated WT dams. We discovered that PE features were significantly suppressed in AT₁-AA-treated Adora2b^-/- dams compared with WT dams.

<Conclusions>

Our results reveled that AT₁-AA-induced placental CD73 promotes the production of Ado leading to the development of PE thorough the activation of ADORA2B.

Antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy complications, which is associated with antiphospholipid (aPL) antibodies. It has been known that several MHC class II (HLA-II) gene polymorphisms are associated with APS, although mechanisms how HLA-II gene polymorphisms regulate APS still have remained unclear. β2-glycoprotein I (β2GPI) is the main phospholipid-binding molecule recognized by aPL antibodies. It is also unclear how β2GPI is recognized by aPL antibodies. On the other hand, Arase et al. has recently found that IgG heavy chain/HLA-II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we found that intracellular β2GPI is transported to the cell surface by HLA-II molecules. Furthermore, human anti-cardiolipin monoclonal antibody (EY2C9) as well as autoantibodies in APS patient’s sera specifically recognized β2GPI complexed with HLA-II molecules of APS-susceptible alleles (HLA-DR7). In addition, 100 of the 120 APS patients (83.3%) analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize β2GPI/HLA-DR7 complexes in the absence of phospholipids. Indeed, β2GPI / HLA-II complexes were detected in endothelial cells of vessels in uterine decidual tissues obtained from APS patients with spontaneous abortion. Furthermore, EY2C9 mediated complement-dependent cytotoxicity against cells expressing β2GPI / HLA-DR7 complex.

These data suggest that β2GPI / HLA-II complexes are involved in pathologies of APS and detection of autoantibodies against β2GPI / HLA-DR7 complex could contribute for better recognition of patients with APS.