title: Activation of Nod1 Signaling Induces Fetal Growth Restriction and Death through Fetal and Maternal Vasculopathy.
abstract: Intrauterine fetal growth restriction (IUGR) and death (IUFD) are both serious problems in the perinatal medicine. Fetal vasculopathy is currently considered to account for a pathogenic mechanism of IUGR and IUFD. We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), contributed to the development of vascular inflammations in mice at postnatal stages. However, little is known about the deleterious effects of activated Nod1 signaling on embryonic growth and development. We report that administration of FK565, one of the Nod1 ligands, to pregnant C57BL/6 mice induced IUGR and IUFD. Mass spectrometry analysis revealed that maternally injected FK565 was distributed to the fetal tissues across placenta. In addition, maternal injection of FK565 induced robust increases in the amounts of CCL2, IL-6, and TNF proteins as well as NO in maternal, placental and fetal tissues. Nod1 was highly expressed in fetal vascular tissues, where significantly higher levels of CCL2 and IL-6 mRNAs were induced with maternal injection of FK565 than those in other tissues. Using Nod1-knockout mice, we verified that both maternal and fetal tissues were involved in the development of IUGR and IUFD. Furthermore, FK565 induced upregulation of genes associated with immune response, inflammation, and apoptosis in fetal vascular tissues. Our data thus provided new evidence for the pathogenic role of Nod1 in the development of IUGR and IUFD at the maternal-fetal interface.
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; hinoue@pediatr.med.kyushu-u.ac.jp.
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Hisanori
authors.identifier: http://orcid.org/0000-0003-3631-7790
authors.initials: H
authors.lastname: Nishio
authors.affiliation: Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Yasunari
authors.identifier: http://orcid.org/0000-0002-5747-8692
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Etsuro
authors.initials: E
authors.lastname: Nanishi
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ochiai
authors.affiliation: Department of Pathophysiological and Experimental Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and.
authors.forename: Mitsuho
authors.identifier: http://orcid.org/0000-0002-1926-2356
authors.initials: M
authors.lastname: Onimaru
authors.affiliation: Department of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Si Jing
authors.identifier: http://orcid.org/0000-0002-7857-1140
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Department of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Toshiro
authors.identifier: http://orcid.org/0000-0002-9137-8417
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D005313:Fetal Death / Q000209:etiology / Q000517:prevention & control*; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000276:immunology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D018811:Maternal Exposure / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage*; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014657:Vasculitis / Q000139:chemically induced / Q000276:immunology*
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D008024:Ligands; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; C039537:heptanoyl-gamma-D-glutamyl-L-meso-diaminopimelyl-D-alanine