Autoantibody against AT1 receptor from preeclamptic patients induces vasoconstriction through angiotensin receptor activation

Abstract

Preeclampsia is a serious pathologic complication during pregnancy, and its pathogenesis remains poorly understood. Recent studies have demonstrated that autoantibodies against angiotensin II type 1A receptor (AT1-AA) are present in women with preeclampsia. However, their role in the development of hypertension in preeclamptic patients has never been previously investigated. The present study was designed to determine whether AT1-AA isolated from the sera of preeclamptic patients causes vascular constriction and, if so, to further investigate the cellular receptors that mediate their vasoactivity. Blood samples were collected from 49 pregnant women (preeclampsia = 31, control = 18) and AT1-AA was detected using enzyme-linked immunosorbent assay. Vasoconstrictive effect of purified IgG from the sera of either preeclamptic patients or normal pregnant women was determined in isolated rat thoracic aorta, arteriae cerebri media and coronary artery. Compared with normal pregnant women, frequency of AT1-AA positive samples was markedly increased in preeclamptic patients (80.7 vs. 5.6%, P < 0.01). In isolated thoracic aortic rings, middle cerebral artery and coronary artery segments, AT1-AA induced vasoconstriction in a concentration-dependent fashion (P < 0.01). The vasoconstrictive effect of AT1-AA was completely blocked by losartan, an AT1-receptor antagonist. These data demonstrate that the AT1-AA causes significant vascular constriction in large conduit vessel as well as small resistant vessels though activation of the AT1 receptor. These results suggest that overproduction of AT1-AA is a novel risk factor in pregnant women and may play a causative role in the development of hypertension and vascular injury in preeclamptic patients.

Endothelial dysfunction induced by antibodies against angiotensin AT1 receptor in immunized rats

“…It has been demonstrated that AT1-AAs increased the expression of tissue factor [24] , induced Ca 2+ release [25] and activated NADPH oxidase [10] in VSMCs [9] . Our research group also found [18] that AT1-AAs could contract capacity blood vessels (thoracic aorta) and resistance blood vessels (coronary, middle cerebral artery) of rats. These studies suggested that AT1-AAs in patients may be closely related to vascular activities.…”

“…So the increase of LDH is often viewed as one of the hallmarks of cell disintegration and necrosis. In order to reduce the interference caused by serum, total IgGs from AT1-Ab positive anti-sera of the immunized rats were purified according to previous studies [18] . Then the immunoglubulins were added to isolated cultured HUVECs, and LDH activity significantly increased after a certain time.…”

“…Modified ELISA was used to detect the titers of AT1-Abs in sera [18] . The procedure was as follows, the synthesized peptide was dissolved in a Na 2 CO 3 solution (pH 11.0).…”

Elevation of Angiotensin-II Type-1-Receptor Autoantibodies Titer in Primary Aldosteronism as a Result of Aldosterone-Producing Adenoma

“…9 Thereafter, studies both in vivo and in vitro showed that AT1AA have biological effects, including Ca 2+ release in vascular smooth muscle cells, NADPH (nicotinamide adenine dinucleotide phosphate) oxidase stimulation, nuclear factor-κB, and JAK-STAT (Janus Kinase and Signal Transducer and Activator of Transcription pathway) activation, and induction of a preeclamptic-like syndrome in pregnant mice. [19][20][21][22][23][24] Circulating autoantibodies against the AT1 were detected in one third of patients with malignant hypertension secondary to renovascular disease, 10 and also in patients with acute renal transplant rejection and malignant hypertension. 12 Altogether these findings suggested that they could be a marker for vascular damage, rather than high BP per se.…”

“…Third, our present data do not directly demonstrate an agonistic activity of AT1AA on AT1 receptors; however, previous studies indicated that increased levels of AT1AAs, as detected by this ELISA assay, cause vascular constriction and other biological effects that are held to occur through activation of AT1 receptor. 21,24 The following strengths are, however, also to be noted: this study was carried out according to the STARD Committee recommendations, 40 in that strict diagnostic criteria based on adrenal vein sampling, pathology, and follow-up information were used for diagnosing APA; moreover, different positive and negative control populations were recruited, and a stateof-the-art statistical analysis was exploited to assess diagnostic accuracy and compare different tests.…”