Angiotensin receptors, autoimmunity, and preeclampsia

Abstract

Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contributes to pathophysiology associated with preeclampsia. The research reviewed here raises the intriguing possibility that preeclampsia may be a pregnancy-induced autoimmune disease.

FIGURE 1

AT1-AA may underlie many features of preeclampsia by interacting with AT1 receptors on different cell types. AT1-AA from preeclamptic patients function as Ang II in the activation of AT1 receptors at the surface of many cell types. Autoantibody-induced AT1 receptor activation results in increased contraction rates in cardiac myocytes, increased production of NADPH oxidase by trophoblast and vascular smooth muscle cells, PAI-1, sFlt-1, and NADPH oxidase by trophoblast cells, PAI-1 and IL-6 production by mesangial cells, and tissue factor by endothelial cells. AT1-AA-mediated AT1 receptor activation also results in the mobilization of intracellular calcium and the activation of NFAT-responsive genes. We propose that AT1-AA activate AT1 receptors on other cell types, resulting in the physiological changes associated with preeclampsia. Note that increased NADPH oxidase activity leads to increased production of reactive oxygen species (ROS). SMC, Smooth muscle cell; EC, endothelial cell.

FIGURE 2

Proposed model of Ang II- and AT1-AA-induced sFlt-1 secretion in normal pregnancy and in preeclampsia. The synthesis and secretion of sFlt-1 is increased late in a normal pregnancy through the action of Ang II (14). We have suggested that the antiangiogenic action of elevated sFlt-1 functions as a brake to inhibit continuing angiogenesis late in pregnancy (14). However, under preeclamptic conditions the additional activation of the AT1 receptor by the maternal circulating AT1-AA results in additional sFlt-1 secretion over that stimulated by Ang II alone. The excessive placenta-derived sFlt-1 has detrimental effects on placental development and maternal vascular and renal function. Our recent results (22) suggest that the excessive production of sFlt-1 can be prevented by the seven-amino acid epitope peptide and that this peptide may have therapeutic potential in the management of preeclampsia. 7-mer, Seven-amino acid epitope peptide.

FIGURE 3

A model to account for autoantibody induction during pregnancy. AT1-AA production is preceded by a maternal inflammatory response to placental ischemia. The decreased blood flow to the placenta in RUPP rats leads to placental ischemia and hypoxia. This may result in endovascular damage, leading to a maternal inflammatory response associated with the increased secretion of inflammatory cytokines (i.e., TNF-α and IL-6). The resulting inflammatory cytokine secretion contributes to AT1-AA production. AT1-AA will directly induce higher blood pressure and proteinuria via AT1 receptor activation. This eventually leads to more hypoxia, endovascular damage, and enhanced inflammatory response, further favoring autoantibody production.