Antibodies from preeclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation

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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ concentrations and changes in gene expression associated with preeclampsia.