ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice

Victoria Ulrich, Shari E. Gelber, Milena Vukelic, Anastasia Sacharidou, Joachim Herz, Rolf T. Urbanus, Philip G. De Groot, David R. Natale, Anirudha Harihara, Patricia Redecha, Vikki M. Abrahams, Philip W. Shaul, Jane E. Salmon, Chieko Mineo

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Objective Pregnancies in women with the antiphospholipid syndrome (APS) are frequently complicated by fetal loss and intrauterine growth restriction (IUGR). How circulating antiphospholipid antibodies (aPL) cause pregnancy complications in APS is poorly understood. We sought to determine whether the low-density lipoprotein receptor family member apolipoprotein E receptor 2 (ApoER2) mediates trophoblast dysfunction and pregnancy complications induced by aPL. Methods Placental and trophoblast ApoER2 expression was evaluated by immunohistochemistry and immunoblotting. Normal human IgG and aPL were purified from healthy individuals and APS patients, respectively. The role of ApoER2 in aPL-induced changes in trophoblast proliferation and migration and in kinase activation was assessed using RNA interference in HTR-8/SVneo cells. The participation of ApoER2 in aPL-induced pregnancy loss and IUGR was evaluated in pregnant ApoER2+/+ and ApoER2-/- mice injected with aPL or normal human IgG. Results We found that ApoER2 is abundant in human and mouse placental trophoblasts and in multiple trophoblast-derived cell lines, including HTR-8/SVneo cells. ApoER2 and its interaction with the cell surface protein β2-glycoprotein I were required for aPL-induced inhibition of cultured trophoblast proliferation and migration. In parallel, aPL antagonism of Akt kinase activation by epidermal growth factor in trophoblasts was mediated by ApoER2. Furthermore, in a murine passive-transfer model of pregnancy complications of APS, ApoER2-/- mice were protected from both aPL-induced fetal loss and aPL-induced IUGR. Conclusion ApoER2 plays a major role in the attenuation of trophoblast function by aPL, and the receptor mediates aPL-induced pregnancy complications in vivo in mice. ApoER2-directed interventions can now potentially be developed to combat the pregnancy complications associated with APS.

Original languageEnglish (US)
Pages (from-to)730-739
Number of pages10
JournalArthritis and Rheumatology
Volume68
Issue number3
DOIs
StatePublished - Mar 1 2016

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Low Density Lipoprotein Receptor-Related Protein-1
Antiphospholipid Antibodies
Pregnancy Complications
Trophoblasts
Antiphospholipid Syndrome
low density lipoprotein receptor-related protein 8
Phosphotransferases
Growth
Immunoglobulin G
Pregnancy
LDL Receptors
RNA Interference
Immunoblotting
Epidermal Growth Factor

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology

Cite this

ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice. / Ulrich, Victoria; Gelber, Shari E.; Vukelic, Milena; Sacharidou, Anastasia; Herz, Joachim; Urbanus, Rolf T.; De Groot, Philip G.; Natale, David R.; Harihara, Anirudha; Redecha, Patricia; Abrahams, Vikki M.; Shaul, Philip W.; Salmon, Jane E.; Mineo, Chieko.

In: Arthritis and Rheumatology, Vol. 68, No. 3, 01.03.2016, p. 730-739.

Research output: Contribution to journalArticle

Ulrich, V, Gelber, SE, Vukelic, M, Sacharidou, A, Herz, J, Urbanus, RT, De Groot, PG, Natale, DR, Harihara, A, Redecha, P, Abrahams, VM, Shaul, PW, Salmon, JE & Mineo, C 2016, 'ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice', Arthritis and Rheumatology, vol. 68, no. 3, pp. 730-739. https://doi.org/10.1002/art.39453
Ulrich, Victoria ; Gelber, Shari E. ; Vukelic, Milena ; Sacharidou, Anastasia ; Herz, Joachim ; Urbanus, Rolf T. ; De Groot, Philip G. ; Natale, David R. ; Harihara, Anirudha ; Redecha, Patricia ; Abrahams, Vikki M. ; Shaul, Philip W. ; Salmon, Jane E. ; Mineo, Chieko. / ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice. In: Arthritis and Rheumatology. 2016 ; Vol. 68, No. 3. pp. 730-739.
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abstract = "Objective Pregnancies in women with the antiphospholipid syndrome (APS) are frequently complicated by fetal loss and intrauterine growth restriction (IUGR). How circulating antiphospholipid antibodies (aPL) cause pregnancy complications in APS is poorly understood. We sought to determine whether the low-density lipoprotein receptor family member apolipoprotein E receptor 2 (ApoER2) mediates trophoblast dysfunction and pregnancy complications induced by aPL. Methods Placental and trophoblast ApoER2 expression was evaluated by immunohistochemistry and immunoblotting. Normal human IgG and aPL were purified from healthy individuals and APS patients, respectively. The role of ApoER2 in aPL-induced changes in trophoblast proliferation and migration and in kinase activation was assessed using RNA interference in HTR-8/SVneo cells. The participation of ApoER2 in aPL-induced pregnancy loss and IUGR was evaluated in pregnant ApoER2+/+ and ApoER2-/- mice injected with aPL or normal human IgG. Results We found that ApoER2 is abundant in human and mouse placental trophoblasts and in multiple trophoblast-derived cell lines, including HTR-8/SVneo cells. ApoER2 and its interaction with the cell surface protein β2-glycoprotein I were required for aPL-induced inhibition of cultured trophoblast proliferation and migration. In parallel, aPL antagonism of Akt kinase activation by epidermal growth factor in trophoblasts was mediated by ApoER2. Furthermore, in a murine passive-transfer model of pregnancy complications of APS, ApoER2-/- mice were protected from both aPL-induced fetal loss and aPL-induced IUGR. Conclusion ApoER2 plays a major role in the attenuation of trophoblast function by aPL, and the receptor mediates aPL-induced pregnancy complications in vivo in mice. ApoER2-directed interventions can now potentially be developed to combat the pregnancy complications associated with APS.",
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T1 - ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice

AU - Ulrich, Victoria

AU - Gelber, Shari E.

AU - Vukelic, Milena

AU - Sacharidou, Anastasia

AU - Herz, Joachim

AU - Urbanus, Rolf T.

AU - De Groot, Philip G.

AU - Natale, David R.

AU - Harihara, Anirudha

AU - Redecha, Patricia

AU - Abrahams, Vikki M.

AU - Shaul, Philip W.

AU - Salmon, Jane E.

AU - Mineo, Chieko

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N2 - Objective Pregnancies in women with the antiphospholipid syndrome (APS) are frequently complicated by fetal loss and intrauterine growth restriction (IUGR). How circulating antiphospholipid antibodies (aPL) cause pregnancy complications in APS is poorly understood. We sought to determine whether the low-density lipoprotein receptor family member apolipoprotein E receptor 2 (ApoER2) mediates trophoblast dysfunction and pregnancy complications induced by aPL. Methods Placental and trophoblast ApoER2 expression was evaluated by immunohistochemistry and immunoblotting. Normal human IgG and aPL were purified from healthy individuals and APS patients, respectively. The role of ApoER2 in aPL-induced changes in trophoblast proliferation and migration and in kinase activation was assessed using RNA interference in HTR-8/SVneo cells. The participation of ApoER2 in aPL-induced pregnancy loss and IUGR was evaluated in pregnant ApoER2+/+ and ApoER2-/- mice injected with aPL or normal human IgG. Results We found that ApoER2 is abundant in human and mouse placental trophoblasts and in multiple trophoblast-derived cell lines, including HTR-8/SVneo cells. ApoER2 and its interaction with the cell surface protein β2-glycoprotein I were required for aPL-induced inhibition of cultured trophoblast proliferation and migration. In parallel, aPL antagonism of Akt kinase activation by epidermal growth factor in trophoblasts was mediated by ApoER2. Furthermore, in a murine passive-transfer model of pregnancy complications of APS, ApoER2-/- mice were protected from both aPL-induced fetal loss and aPL-induced IUGR. Conclusion ApoER2 plays a major role in the attenuation of trophoblast function by aPL, and the receptor mediates aPL-induced pregnancy complications in vivo in mice. ApoER2-directed interventions can now potentially be developed to combat the pregnancy complications associated with APS.

AB - Objective Pregnancies in women with the antiphospholipid syndrome (APS) are frequently complicated by fetal loss and intrauterine growth restriction (IUGR). How circulating antiphospholipid antibodies (aPL) cause pregnancy complications in APS is poorly understood. We sought to determine whether the low-density lipoprotein receptor family member apolipoprotein E receptor 2 (ApoER2) mediates trophoblast dysfunction and pregnancy complications induced by aPL. Methods Placental and trophoblast ApoER2 expression was evaluated by immunohistochemistry and immunoblotting. Normal human IgG and aPL were purified from healthy individuals and APS patients, respectively. The role of ApoER2 in aPL-induced changes in trophoblast proliferation and migration and in kinase activation was assessed using RNA interference in HTR-8/SVneo cells. The participation of ApoER2 in aPL-induced pregnancy loss and IUGR was evaluated in pregnant ApoER2+/+ and ApoER2-/- mice injected with aPL or normal human IgG. Results We found that ApoER2 is abundant in human and mouse placental trophoblasts and in multiple trophoblast-derived cell lines, including HTR-8/SVneo cells. ApoER2 and its interaction with the cell surface protein β2-glycoprotein I were required for aPL-induced inhibition of cultured trophoblast proliferation and migration. In parallel, aPL antagonism of Akt kinase activation by epidermal growth factor in trophoblasts was mediated by ApoER2. Furthermore, in a murine passive-transfer model of pregnancy complications of APS, ApoER2-/- mice were protected from both aPL-induced fetal loss and aPL-induced IUGR. Conclusion ApoER2 plays a major role in the attenuation of trophoblast function by aPL, and the receptor mediates aPL-induced pregnancy complications in vivo in mice. ApoER2-directed interventions can now potentially be developed to combat the pregnancy complications associated with APS.

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