摘要
Background Preeclampsia is a serious disorder of pregnancy characterized by h ypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in pla telets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT1) receptors are also highly associat ed with preeclampsia. Methods and Results We tested the hypothesis that AT1 rec eptor agonistic antibodies(AT1 AAs) could activate AT1 receptors, leading to a n increased intracellular concentration of free calcium and to downstream activa tion 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 preeclampti c patients activated AT1 receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT1 receptors. The specific mobilization of intracellular Ca2+by AT1 AAs was bloc ked by losartan, an AT1 receptor antagonist, and by a 7 amino acid peptide tha t corresponds to a portion of the second extracellular loop of the AT1 receptor. In addition, we have shown that AT1 AA stimulated mobilization of intracellul ar 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 AT1 receptors are likely to account for increased intracel lular free Ca2+concentrations and changes in gene expression associated with pr eeclampsia.
Background Preeclampsia is a serious disorder of pregnancy characterized by h ypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in pla telets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT1) receptors are also highly associat ed with preeclampsia. Methods and Results We tested the hypothesis that AT1 rec eptor agonistic antibodies(AT1 AAs) could activate AT1 receptors, leading to a n increased intracellular concentration of free calcium and to downstream activa tion 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 preeclampti c patients activated AT1 receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT1 receptors. The specific mobilization of intracellular Ca2+by AT1 AAs was bloc ked by losartan, an AT1 receptor antagonist, and by a 7 amino acid peptide tha t corresponds to a portion of the second extracellular loop of the AT1 receptor. In addition, we have shown that AT1 AA stimulated mobilization of intracellul ar 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 AT1 receptors are likely to account for increased intracel lular free Ca2+concentrations and changes in gene expression associated with pr eeclampsia.
