Extravillous trophoblasts (EVT) of the human placenta invade the uterine decidua and its arteries to ensure successful placentation. We previously identified two decidua-derived molecules, TGF-β and a TGF-β-binding proteoglycan decorin (DCN), as negative regulators of EVT proliferation, migration, and invasiveness and reported that DCN acts via multiple tyrosine kinase receptors [epidermal growth factor-receptor (EGF-R), IGF receptor-1 (IGFR1), and vascular endothelial growth factor 2 receptor (VEGFR-2)]. Because binding of DCN to VEGFR-2 has never been reported earlier, present study explored this binding, the approximate location of VEGFR-2-binding site in DCN, and its functional role in our human first trimester EVT cell line HTR-8/SVneo. Based on far-Western blotting and coimmunoprecipitation studies, we report that DCN binds both native (EVT expressed) and recombinant VEGFR-2 and that this binding is abrogated with a VEGFR-2 blocking antibody, indicating an overlap between the ligand-binding and the DCN-binding domains of VEGFR-2. We determined that (125)I-labeled VEGF-E (a VEGFR-2 specific ligand) binds EVT with a dissociation constant (K(d)) of 566 pM, and DCN displaced this binding with an inhibition constant (K(i)) of 3.93-5.78 nM, indicating a 7- to 10-fold lower affinity of DCN for VEGFR-2. DCN peptide fragments derived from the leucine rich repeat 5 domain that blocked DCN-VEGFR-2 interactions or VEGF-E binding in EVT cells also blocked VEGF-A- and VEGF-E-induced EVT cell proliferation and migration, indicative of functional VEGFR-2-binding sites of DCN. Finally, DCN inhibited VEGF-E-induced EVT migration by interfering with ERK1/2 activation. Our findings reveal a novel role of DCN as an antagonistic ligand for VEGFR-2, having implications for pathophysiology of preeclampsia, a trophoblast hypoinvasive disorder in pregnancy, and explain its antiangiogenic function.

Incubation of platelet-rich plasma with 80 microM aspirin that resulted in the inhibition of both the secondary phase of ADP induced platelet aggregation and prostaglandin synthesis simultaneously stimulated the production of NO in platelets. Furthermore it was found that the treatment of platelet-rich plasma either with 80 microM ibuprofen or salicylic acid, like aspirin, which inhibited the secondary phase of platelet aggregation by ADP and prostaglandin synthesis, also stimulated the production of NO in the absence of added ADP. However the inhibition of prostaglandin synthesis by ibuprofen or salicylic acid, unlike aspirin, was transient in nature. Incubation of washed platelets with any of these three compounds also stimulated NO synthesis indicating that the effect of these compounds was not mediated through plasma proteins. The in vitro effect of aspirin on the increase of NO in platelets could also be demonstrated by in vivo exposure of platelets to the compound. It was concluded that either a temporary or a lasting inhibition of prostaglandin synthesis by these inhibitors resulted in the synthesis of NO in resting platelets. Since NO is a potent inhibitor of platelet aggregation the inhibition of platelet aggregation, by these compounds may not be the consequence of the inhibition of prostaglandin synthesis alone, but could also be related, at least partly, to the stimulated synthesis of NO by these inhibitors.

Coronavirus disease 2019 (COVID-19) has spread rapidly throughout the world. The range of the disease is broad but among hospitalized patients with COVID-19 are coagulation disorders, pneumonia, respiratory failure, and acute respiratory distress syndrome (ARDS). The excess production of early response proinflammatory cytokines results in what has been described as a cytokine storm, leading to an increased risk of thrombosis, inflammations, vascular hyperpermeability, multi-organ failure, and eventually death over time. As the pandemic is spreading and the whole picture is not yet clear, we highlight the importance of coagulation disorders in COVID-19 infected subjects and summarize it. COVID-19 infection could induce coagulation disorders leading to clot formation as well as pulmonary embolism with detrimental effects in patient recovery and survival. Coagulation and inflammation are closely related. In this review, we try to establish an association between virus infections associated with innate immune activation, inflammation and coagulation activation.

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It was found that the resumption of NO synthesis through the neutralization of antibody resulted in favorable modifications of various cancer-associated pathophysiologic consequences.

Increased plasma level of von Willebrand Factor (vWF) is associated with major cardiovascular diseases. We previously reported that multimeric vWF binds to NO synthase and inhibits insulin-induced production of NO, thus promoting insulin resistance during acute hypoxia (AH). However, the transcriptional regulation of vWF during AH is not clearly understood. Here, we investigated the mechanisms underlying the upregulation of vwf in mice. AH significantly upregulates the tlr2, tlr3, myd88, and vwf expression and phosphorylation of specificity protein 1 (SP1). Furthermore, AH significantly upregulates high mobility group box-1 (HMGB1) in a time-dependent manner. Moreover, a TLR2 agonist upregulates vWF but a TLR3 agonist does not. Pretreatment with an HMGB1 inhibitor, TLR2-immunoneutralizing antibody, or SP1 inhibitor significantly inhibits vWF expression. Furthermore, Tlr2 silencing completely inhibited MYD88, vWF expression, and SP1 phosphorylation. However, pretreatment with glycyrrhizic acid or silencing of Tlr2 completely blocks binding of Sp1 to the Vwf promoter, thus inhibiting its expression, and enhances insulin resistance during AH. Patients with type 2 diabetes mellitus also showed significantly elevated levels of HMGB1, TLR2, SP1, and vWF, thereby supporting the results of the murine model of AH. Taken together, HMGB1 upregulates vWF in vivo through the TLR2-MYD88-SP1 pathway in mice.

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