Antibodies From Preeclamptic Patients Stimulate Increased Intracellular Ca ²⁺ Mobilization Through Angiotensin Receptor Activation

Abstract

Background-Preeclampsia is a serious disorder of pregnancy characterized by hypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in platelets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT 1 ) receptors are also highly associated with preeclampsia. Methods and Results-We tested the hypothesis that AT 1 receptor-agonistic antibodies (AT 1 -AAs) could activate AT 1 receptors, leading to an increased intracellular concentration of free calcium and to downstream activation of Ca 2ϩ signaling pathways. Sera of 30 pregnant patients, 16 diagnosed with severe preeclampsia and 14 normotensive, were examined for the presence of IgG capable of stimulating intracellular Ca 2ϩ mobilization. IgG from all preeclamptic patients activated AT 1 receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT 1 receptors. The specific mobilization of intracellular Ca 2ϩ by AT 1 -AAs was blocked by losartan, an AT 1 receptor antagonist, and by a 7-amino-acid peptide that corresponds to a portion of the second extracellular loop of the AT 1 receptor. In addition, we have shown that AT 1 -AA-stimulated mobilization of intracellular Ca 2ϩ results in the activation of the transcription factor, nuclear factor of activated T cells. Conclusions-These results suggest that maternal antibodies capable of activating AT 1 receptors are likely to account for increased intracellular free Ca 2ϩ concentrations and changes in gene expression associated with preeclampsia. Key Words: autoimmunity Ⅲ antibodies Ⅲ signal transduction Ⅲ hypertension Ⅲ pregnancy P reeclampsia is a pregnancy-induced hypertensive disorder that affects Ϸ3% to 5% of first pregnancies and is a leading cause of maternal and fetal mortality and morbidity. This disorder is characterized by the development of a maternal syndrome that includes hypertension, coagulation abnormalities, edema, proteinuria, and vascular abnormalities. These symptoms normally develop after 20 weeks of gestation and disappear within 7 to 10 days after delivery. However, subtle signs, such as increased protein excretion, may persist for several months. The main target organs affected in preeclampsia are the brain, kidneys, liver, lungs, placenta, and heart. Advanced stages of the disease include cerebral hemorrhage, renal failure, and the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). Two well-known pathogenic features of preeclampsia are placental and vascular abnormalities. Shallow trophoblast invasion and improper remodeling of spiral arteries are among the bestrecognized and most frequently associated features of this disease. Altered levels of circulating vasoactive substances, such as endothelin and prostaglandins, have been reported in preeclampsia. 1 Preeclampsia is also associated with abnormalities in Ca 2ϩ metabolism and increased ...

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