Preeclampsia is a pregnancy-specific condition characterized by new-onset hypertension and proteinuria associated with placental ischemia. Because no cure exists besides parturition, preeclampsia remains a leading cause of maternal and perinatal death and morbidity. New management strategies are urgently needed to attenuate maternal symptoms and prolong gestation. Immune activity is normally heightened in pregnancy and has been shown to increase even further in preeclampsia, as evidenced by elevations in innate immune complement activation products, including C3a. Decreased circulating free vascular endothelial growth factor (VEGF) is a known contributor to preeclampsia and previous studies have demonstrated a link between VEGF and complement. We therefore hypothesized that complement activation is critical to placental ischemia-induced hypertension. To test this, we used the Reduced Utero-placental Perfusion Pressure (RUPP) model of placental ischemia in the rat to induce hypertension and explore the effects of inhibiting complement activation and antagonizing a specific complement receptor in this model. The data demonstrate that complement activation occurred following placental ischemia and administration of soluble complement receptor 1, an inhibitor of complement activation, successfully prevented complement activation and abrogated the hypertension without influencing circulating free VEGF concentrations. To determine the specific complement component responsible, we used a C3a receptor antagonist to inhibit C3a-mediated cellular responses that may be important in placental ischemia-induced hypertension. The C3a receptor antagonist attenuated the hypertension and improved placental efficiency and did not affect circulating free VEGF, suggesting complement may be important in hypertension apart from circulating free VEGF concentrations. Overall, these data suggest a potentially valuable role for specific complement inhibition in managing the symptoms of preeclampsia.
University of Minnesota M.S. thesis. October 2013. Major: Integrated Biosciences. Advisor: Jean F. Regal. 1 computer file (PDF); vii, 100 pages.
Lillegard, Kathryn Elisabeth.
The role of complement system activation in placental ischemia-induced hypertension.
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