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21 August 2013 Potential New Mechanisms of Placental Damage in Celiac Disease: Anti-Transglutaminase Antibodies Impair Human Endometrial Angiogenesis
Nicoletta Di Simone, Marco De Spirito, Fiorella Di Nicuolo, Chiara Tersigni, Roberta Castellani, Marco Silano, Giuseppe Maulucci, Massimiliano Papi, Riccardo Marana, Giovanni Scambia, Antonio Gasbarrini
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Abstract

Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion and characterized by circulating anti-transglutaminase type 2 (anti-TG2) autoantibodies. An epidemiological link between maternal CD and increased risk of pregnancy failure has been established; however, the mechanism underlying this association is still poorly understood. Because proper endometrial angiogenesis and decidualization are prerequisites for placental development, we investigated the effect of anti-TG2 antibodies on the process of endometrial angiogenesis. Binding of anti-TG2 antibodies to human endometrial endothelial cells (HEECs) was evaluated by ELISA. Angiogenesis was studied in vitro on HEECs and in vivo in a murine model. In particular, we investigated the effect of anti-TG2 antibodies on HEEC matrix metalloprotease-2 (MMP-2) activity by gelatin zymography, cytoskeletal organization and membrane properties by confocal microscopy, and activation of extracellular signal-regulated kinases (ERKs) and focal adhesion kinase (FAK) by Western blot analysis. Anti-TG2 antibodies bound to HEECs and decreased newly formed vessels both in vitro and in vivo. Anti-TG2 antibodies impaired angiogenesis by inhibiting the activation of MMP-2, disarranging cytoskeleton fibers, changing the physical and mechanical properties of cell membranes, and inhibiting the intracellular phosphorylation of FAK and ERK. Anti-TG2 antibodies inhibit endometrial angiogenesis affecting the TG2-dependent migration of HEECs and extracellular matrix degradation, which are necessary to form new vessels. Our results identify pathogenic mechanisms of placental damage in CD.

Nicoletta Di Simone, Marco De Spirito, Fiorella Di Nicuolo, Chiara Tersigni, Roberta Castellani, Marco Silano, Giuseppe Maulucci, Massimiliano Papi, Riccardo Marana, Giovanni Scambia, and Antonio Gasbarrini "Potential New Mechanisms of Placental Damage in Celiac Disease: Anti-Transglutaminase Antibodies Impair Human Endometrial Angiogenesis," Biology of Reproduction 89(4), (21 August 2013). https://doi.org/10.1095/biolreprod.113.109637
Received: 4 April 2013; Accepted: 1 July 2013; Published: 21 August 2013
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