Complement activation induces dysregulation of angiogenic factors and causes fetal loss



Complement is an important effector in pregnancy loss in the antiphospholipid syndrome. We now test the hypothesis that complement activation is a necessary intermediary event in the pathogenesis of recurrent spontaneous miscarriage in DBA/2-mated female CBA/J mice (CBAxDBA), a well-studied model of autoantibody-independent pregnancy failure. Blockade of C3 activation with Crry-Ig completely rescued pregnancies in CBAxDBA mice (Crry-Ig vs untreated 8.5 ± 6.3% fetal resorptions vs 28.0 ± 7.2%, P < 0.01). Inhibition of C5 cleavage with anti-C5 mAb and blockade of C5a receptors with a peptide antagonist also prevented pregnancy loss (8.6 ± 4.4% and 8.0 ± 5.9% resorptions, respectively, P < 0.01 versus control). Inhibition of the alternative pathway resulted in pregnancy outcomes similar to controls (8.4 ± 6.6% versus 9.2 ± 3.2% resorptions). In CBAxDBA matings, we observed elevated plasma levels of soluble VEGF receptor-1 (sVEGFR-1; a potent anti-angiogenic molecule), increased placental inflammatory infiltrates and defective development of placenta. Our complement inhibitory strategies blocked the increase in sVEGFR-1, prevented functional deficiency of VEGF and rescued pregnancies. We confirmed the importance of complement as a proximal effector in in vitro studies; monocytes stimulated with C5a released sVEGFR-1 which sequesters VEGF required for normal placental development. Our data indicate that complement activation leads to recruitment of inflammatory cells and production of inhibitors of angiogenesis (sVEGFR-1) which cause placental dysfunction and fetal injury. These studies identify key innate immune effectors that mediate poor pregnancy outcomes and provide novel and important targets for prevention of recurrent pregnancy loss in patients.