Antiphospholipid Antibodies Affect Human Endometrial Angiogenesis1

Abstract

Antiphospholipid antibodies (aPL) represent an important risk factor for thrombosis and recurrent miscarriage in patients with antiphospholipid syndrome (APS). The mechanisms of aPL-mediated pregnancy failure have been researched. Previous studies demonstrated that aPL bind trophoblast cells, reducing proliferation, human chorionic gonadotrophin release, and in vitro invasiveness. Recent data suggest that aPL are also able to react with human decidual cells, inducing a proinflammatory phenotype. Decidua, a newly formed tissue on the maternal side of the human placenta, is characterized by active angiogenesis and structural modifications of the spiral arteries in early pregnancy. Since angiogenesis is a critical component of normal placentation, the purpose of our study was to evaluate the role of aPL on human endometrial angiogenesis. For this reason, we investigated the effect of aPL on in vitro endometrial endothelial cell (HEEC) angiogenesis, VEGF secretion by ELISA, matrix metalloproteinases (MMPs) activity by gelatin zymography, and DNA binding activity of NFKB by a sensitive multiwell colorimetric assay. Furthermore, we performed experiments to study whether aPL affects in vivo angiogenesis in a murine model. We found that aPL significantly decrease the number and the total length of the tubules formed by HEEC on in vitro Matrigel assay and reduce newly formed vessels in aPL-inoculated mice. Moreover, aPL reduce significantly both VEGF and MMPs production and, at the nuclear level, NFKB DNA binding activity. From our results, it appears that aPL are associated with an inhibition of angiogenesis, suggesting further additional mechanisms to explain the defective placentation in the APS.

Beta-2 GPI induced tissue factor and placental apoptosis for the pathophysiology of pregnancy loss in antiphospholipid syndrome

“…These processes are triggered by the interaction of pathogenic aPL with monocytes, endothelial cells (EC), platelets, trophoblast and endometrial cells, as well as plasma components of the coagulation cascade. 16,17,[26][27][28] Therefore, understanding the proposed hypothesis would stand for a growing evidence for the importance of placental apoptosis through TLRs in the pathogenesis of aPL-mediated pregnancy loss. Pathogenic aPL bind to phospholipid binding proteins of which β2GPI is the best characterized.…”

Antiphospholipid Syndrome - An Evolving Story of a Multisystemic Disease

“…Inhibition of endometrial angiogenesis by aPL antibodies has been demonstrated in a recent study assessing in vitro human endometrial endothelial cell (HEEC) angiogenesis and in vivo angiogenesis in a murine model. Human polyclonal IgG aPL antibodies were shown to significantly decrease the number and total length of tubule formation, VEGF and MMP production and NF-B DNA binding activity in HEEC and to reduce new vessel formation in inoculated mice [153].…”

Management of Women with Recurrent Pregnancy Losses and Antiphospholipid Antibody Syndrome

“…Histopathological examination of products of conception in women with pAPS and pregnancy losses between 7 and 10 weeks gestation attributed these losses to abnormal endovascular trophoblast invasion in decidual vessels rather than excessive villous thrombosis. 35 This finding suggests that aPL cause defective placentation, 36 and that thrombophilia is not the sole explanation for complications of pregnancy in patients with APS. Indeed, antib 2 GPI antibodies have been reported to trigger an inflammatory response in trophoblast cells by increasing secretion of IL-8, MCP-1, GRO-a, and IL-1b.…”

“…38 aPL significantly reduce both VEGF and MMPs production, and at the nuclear level, NFjB DNA binding activity. 36 aPL recognize anionic phospholipids and b 2 GPI, which have adhered onto trophoblast cell structures, and significantly reduce bhCG release and Matrigel invasiveness. 39 Therefore, aPL can impair trophoblast cell maturation, mobility, and invasiveness as well.…”

“…aPL has been shown to have a direct effect on trophoblasts unrelated to thrombosis and may induce direct cellular injury, apoptosis, inhibition of proliferation and syncytia formation, decreased human chorionic gonadotropin production, and defective invasiveness. 35,36,52,53 All of these aPL-mediated effects might play a role in defective placentation. Heparin was reported to suppress some of these aPL-related pathology but not all.…”