Lysophosphatidic acid (LPA) is one of the simplest glycerophospholipids with one fatty acid chain and a phosphate group as a polar head. Although LPA had been viewed just as a metabolic intermediate in de novo lipid synthetic pathways, it has recently been paid much attention as a lipid mediator. LPA exerts many kinds of cellular processes, such as cell proliferation and smooth muscle contraction, through cognate G protein-coupled receptors. Because lipids are not coded by the genome directly, it is difficult to know their patho- and physiological roles. However, recent studies have identified several key factors mediating the biological roles of LPA, such as receptors and producing enzymes. In addition, studies of transgenic and gene knockout animals for these LPA-related genes, have revealed the biological significance of LPA. In this review we will summarize recent advances in the studies of LPA production and its roles in both physiological and pathological conditions.

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Scribble (Scrib) is a scaffold protein with multifunctional roles in PCP, tight junction and Hippo signaling. This study shows that Scrib is expressed in stromal cells around the implantation chamber following implantation. Stromal cells transform into epithelial-like cells to form the avascular primary decidual zone (PDZ) around the implantation chamber (crypt). The PDZ creates a permeability barrier around the crypt restricting immune cells and harmful agents from maternal circulation to protect embryonic health. The mechanism underlying PDZ formation is not yet known. We found that uterine deletion of Scrib by a Pgr-Cre driver leads to defective PDZ formation and implantation chamber (crypt) formation, compromising pregnancy success. Interestingly, epithelial-specific Scrib deletion by a lactoferrin-Cre (Ltf-Cre) driver does not adversely affect PDZ formation and pregnancy success. These findings provide evidence for a previously unknown function of stromal Scrib in PDZ formation, potentially involving ZO-1 and Hippo signaling.

During pregnancy, up‐regulation of heparin‐binding (HB‐) EGF and cyclooxygenase‐2 (COX‐2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G‐protein‐coupled receptor LPA 3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA‐producing enzyme autotaxin (ATX) in pregnant mice leads to HB‐EGF and COX‐2 down‐regulation near embryos and attenuates decidual reactions. Conversely, selective pharmacological activation of LPA 3 induces decidualization via up‐regulation of HB‐EGF and COX‐2. ATX and its substrate lysophosphatidylcholine can be detected in the uterine epithelium and in pre‐implantation‐stage embryos, respectively. Our results indicate that ATX–LPA–LPA 3 signaling at the embryo‐epithelial boundary induces decidualization via the canonical HB‐EGF and COX‐2 pathways.

respiratory syndrome coronavirus 2, but it can also cause thromboembolic complications through coagulopathy. 3,4 In particular, several studies reported a high prevalence of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) in hospi-T he coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in December 2019, and has become a huge threat worldwide as a pandemic. 1,2 The main pathophysiology of COVID-19 is a respiratory infectious disease caused by the severe acute

Purpose: Venous thromboembolism prophylaxis is crucial. To facilitate active ankle movement in postoperative and bedridden patients, we developed a novel leg exercise apparatus (LEX). We investigated the effect of the LEX by comparing increases in lower extremity venous flow during different modes of exercise using the LEX. Methods: In eight healthy participants, we measured venous flow volume and velocity in the femoral vein using duplex ultrasonography at 1, 10, 20, and 30 min after completing three modes of 1-min LEX exercises. The exercises involved (1) rapid single motion (ankle dorsi-plantar flexion; 60 cycles/min); (2) slow single motion (30 cycles/min); and (3) slow combined leg motion. Results: Flow volumes after modes 1, 2, and 3 were 1.63-, 1.39-, and 1.53-fold above baseline at 30 min, respectively. Short periods of rapid single motion, with the LEX, improved postexercise lower extremity venous flow volumes at 30 min and mean venous flow velocity at 20 min, compared to slow single motion exercise. Even at slow speeds, combinedmotion improved flow volume compared to single motion. Conclusion: Short periods of rapid single motion exercise, with the LEX, improved postexercise venous flow volumes in the lower extremities at 30 min and mean venous flow velocity at 20 min. These effects were greater than those produced by slow single motion exercises. However, even at slow speeds, combined-motion exercises improved flow volume compared to single motion. Therefore, LEX may prove effective at preventing thromboembolism in postoperative and bedridden patients.

Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.

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