The Role of Angiotensin II Receptor Type I Auto-Antibodies in Pre-Eclampsia
Introduction. Pre-eclampsia is a two part disease of pregnancy whereby failure of the placenta to perfuse leads to systemic effects, including maternal hypertension and proteinuria, and may progress to eclampsia and possible death of mother and fetus1. In the US, rates of pre-eclampsia are between 5-7% of pregnant women2. Risk factors include obesity, diabetes mellitus, smoking, and pre-existing hypertension3. The current curative treatment for pre-eclampsia is delivery and administration of magnesium to prevent seizures4. The Renin Angiotensin System (RAS) has long been thought to play a role in the development of pre-eclampsia. Angiotensin II (ATII) acts as an important hormone in blood pressure modulation, normally functioning to increase blood pressure by acting at the ATII Receptor Type I (AT1) subunit and causing vasoconstriction when the body becomes hypotensive4. However, in the pre-eclamptic patient, hypersensitivity to ATII and generation of autoantibodies to the AT1 receptor (AT1-AA) have been observed and may mediate the pathogenesis of malignant placental hypertension3, 4. Methods. Human placental vessels (HPV) and human umbilical vessels (HUV) were obtained post birth, exposed to angiotensin II (ATII) or phenylephrine (PE) as a control. Resulting vessel wall tension was measured as a metric of constriction5. Another study used a transgenic mouse model to increase the expression of AT1-Bradykinin 2 (B2) mechanosensitive heteromer, and measured subsequent levels of AT1-AA4. Two additional studies investigated the effects of reduced uterine perfusion pressure (RUPP) as a way to induce AT1-AA in a rat model, and measured resulting effects on mean arterial pressure (MAP), natural killer (NK) cells, and reactive oxygen species (ROS). Researchers also administered a modified and capped peptide, n7AAc, in one group of RUPP rats, to bind to circulating AT1-AAs6,7. Results. AT II preferentially constricts HPV versus HUV5. Upregulation of the complex formation between AT1 and B2 is caused by mechanical forces of the fetus in combination with pre-existing risk factors, and leads to increased AT1-AA formation4. Finally, MAP, NK cells, and renal ROS are higher in AT1-AA rats than in normal and AT1-AA + n7AAc groups6, 7. Conclusions. AT1 receptors play an important role in placental vasoconstriction. Increased mechanical forces in late pregnancy contribute to AT1-B2 heteromer formation, which induces AT1-AA to form in the placental circulation. AT1-AAs agonize AT1 to cause vasoconstriction and increase MAP and activate NK cells, which in turn leads to ROS damage in the kidney and further failure of the RAS to regulate placental hypertension, leading to pre-eclampsia.
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