Body Mass Index and recurrent pregnancy loss

TIFI is a synthetic peptide of viral origin from human Cytomegalovirus. It has been introduced in studies performed to evaluate the role of different viral/bacterial products in the production of antiphospholipid antibodies (aPL). Recently, the molecular mimicry between infective agents and host proteins has been proposed as the mechanism by which aPL are produced and exert their pathogenic effect. It has been shown that animal models immunized with TIFI produce significantly higher levels of aPL and anti-2Glycoprotein I (2GPI) compared with the control groups and that such antibodies are similarly pathogenic both in vitro and in vivo being able to induce the clinical manifestations of antiphospholipid syndrome (APS). TIFI shares structural similarity with the Vth domain of 2GPI, believed to be the PL-binding site of the protein. It has been observed that TIFI is able to reverse the aPL-mediated thrombosis in mice. This observation suggested that this viral peptide, through its PL binding site, might prevent aPL from binding to PL and as a consequence migh reverse the aPL mediated effects. In the last years several mechanisms by which aPL may induce defective placentation have been suggested. Among these the inhibition of angiogenesis has been demonstrated as a possible mechanism able to explain the APS obstetrical complications. We previously reported that aPL may reduce the process of angiogenesis both in vitro, by inhibiting the expression of specific factors involved in this process (i.e. Vascular Endothelial Growth Factor, VEGF, and Matrix Metalloproteases, MMPs), and in vivo. Objectives/hypothesis The purpose of our study was to evaluate the role of TIFI and aPL on human endometrial angiogenesis. Methods: For this reason, we investigated the effect of TIFI and aPL on in vitro endometrial endothelial cell (HEEC) angiogenesis, VEGF secretion by ELISA, MMPs activity by gelatine zymography, the expression of ERK by western blot analysis and finally the NFkB DNA-binding activity by a sensitive multiwell colorimetric assay. Furthermore we performed experiments to evaluate whether aPL and TIFI affect in vivo angiogenesis in a murine model. Results: We found that TIFI was able to restore the aPL mediated inhibitory effect on endometrial angiogenesis both in vitro and in vivo. Such abrogation was also observed in VEGF secretion, MMPs activity, ERK activation and NFkB binding activity. From our results, it appears that TIFI is able to restore the aPL-reduced angiogenesis both in vitro and in vivo. Discussion: Our observations suggested that TIFI ability to restore aPL actions on endometrial angiogenesis might be attributable to the competition of TIFI with 2GPI on PL site in HEEC.