The antiphospholipid antibodies (aPL)-mediated inhibition of endometrial angiogenesis. Is there a role for Low Molecular Weight Heparins?

Antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity and circulating aPL. A direct effect of aPL on trophoblast and HEEC has been proposed to explain the aPL-mediated pregnancy failure. Indeed, bound aPL induce trophoblast and HEEC dysfunction. APS patients can be treated with LMWH, which may act through mechanisms alternative to anticoagulation. We previously showed that LMWH reduces aPL binding to trophoblasts and restore cells functions. So far, however, no study has described its effects on endometrial angiogenesis. Aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. METHODS:We investigated:(i)in vitro HEEC angiogenesis through a Matrigel assay; (ii)VEGF secretion by ELISA;(iii)MMP-2 activity by gelatin zymography; (iv)Nuclear Factor-kB (NF-kB) DNA binding activity by colorimetric assay; (v)STAT-3 activation by a sandwich-ELISA; (vi)LMWHs effect in a murine model of in vivo angiogenesis. RESULTS:addition of LMWHs prevents aPL-inhibited HEEC in vitro (Fig1A-B) and in vivo angiogenesis (Fig2) and is able to restore the aPL inhibited NF-kB and/or STAT-3 activity, the VEGF secretion and the MMP2 activity. CONCLUSIONS:The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in APS.