title: Imaging of activated complement using ultrasmall superparamagnetic iron oxide particles (USPIO)--conjugated vectors: an in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development.
abstract: In the current study, we have developed a magnetic resonance imaging-based method for non-invasive detection of complement activation in placenta and foetal brain in vivo in utero. Using this method, we found that anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles bind within the inflamed placenta and foetal brain cortical tissue, causing a shortening of the T2* relaxation time. We used two mouse models of pregnancy complications: a mouse model of obstetrics antiphospholipid syndrome (APS) and a mouse model of preterm birth (PTB). We found that detection of C3 deposition in the placenta in the APS model was associated with placental insufficiency characterised by increased oxidative stress, decreased vascular endothelial growth factor and placental growth factor levels and intrauterine growth restriction. We also found that foetal brain C3 deposition was associated with cortical axonal cytoarchitecture disruption and increased neurodegeneration in the mouse model of APS and in the PTB model. In the APS model, foetuses that showed increased C3 in their brains additionally expressed anxiety-related behaviour after birth. Importantly, USPIO did not affect pregnancy outcomes and liver function in the mother and the offspring, suggesting that this method may be useful for detecting complement activation in vivo in utero and predicting placental insufficiency and abnormal foetal neurodevelopment that leads to neuropsychiatric disorders.
authors.affiliation: 1] MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK [2] Lupus Research Unit, The Rayne Institute, King's College London St Thomas' Hospital, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Girardi
authors.affiliation: Centre for Nano Safety, Napier University Edinburgh, Edinburgh, UK.
authors.forename: J
authors.initials: J
authors.lastname: Fraser
authors.affiliation: BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: R
authors.initials: R
authors.lastname: Lennen
authors.affiliation: Centrer for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, The Rayne Institute, King's College London, St Thomas' Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Vontell
authors.affiliation: BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Centre for Nano Safety, Napier University Edinburgh, Edinburgh, UK.
authors.forename: G
authors.initials: G
authors.lastname: Hutchison
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D001007:Anxiety / Q000503:physiopathology; D001921:Brain / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D003176:Complement C3 / Q000378:metabolism; D003287:Contrast Media / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005290:Ferric Compounds / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D053758:Nanoparticles / Q000378:metabolism; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D010927:Placental Insufficiency / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011256:Pregnancy Outcome
chemical_list: D017152:Antibodies, Antiphospholipid; D003176:Complement C3; D003287:Contrast Media; D005290:Ferric Compounds; D008070:Lipopolysaccharides; C082161:lipopolysaccharide A; C000499:ferric oxide