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¹ Autoimmunity and Inflammation Program, Hospital for Special Surgery, Weill Medical College, Cornell University, New York, NY 10021
² Department of Medicine and Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262

CORRESPONDENCE Jane E. Salmon: salmonj{at}hss.edu

Immune mechanisms have been implicated in placental dysfunction in patients with recurrent miscarriages and intrauterine growth restriction (IUGR), but the mediators are undefined. Here we show that complement activation, particularly C5a, is a required intermediary event in the pathogenesis of placental and fetal injury in an antibody-independent mouse model of spontaneous miscarriage and IUGR, and that complement activation causes dysregulation of the angiogenic factors required for normal placental development. Pregnancies complicated by miscarriage or growth restriction were characterized by inflammatory infiltrates in placentas, functional deficiency of free vascular endothelial growth factor (VEGF), elevated levels of soluble VEGF receptor 1 (sVEGFR-1, also known as sFlt-1; a potent anti-angiogenic molecule), and defective placental development. Inhibition of complement activation in vivo blocked the increase in sVEGFR-1 and rescued pregnancies. In vitro stimulation of monocytes with products of the complement cascade directly triggered release of sVEGFR-1, which sequesters VEGF. These studies provide the first evidence linking the complement system to angiogenic factor imbalance associated with placental dysfunction, and identify a new effector of immune-triggered pregnancy complications.

Abbreviations used: Crry, complement receptor 1–related gene/protein y; HRP, horseradish peroxidase; IC, immune complex; IUGR, intrauterine growth restriction; PEG sTNFRI, polyethylene glycol–conjugated soluble TNF- receptor type I; sVEGFR-1, soluble vascular endothelial growth factor receptor 1; VEGF, vascular endothelial growth factor; VEGFR-1, VEGF receptor 1.

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