AT1-AA infusion during pregnancy impairs CBF autoregulation postpartum

Preeclampsia (PE), new-onset hypertension during pregnancy alongside organ dysfunction, is a leading cause of morbidity and mortality for the mother and fetus. PE women have activated B cells that produce agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA impairs cerebral blood flow (CBF) autoregulation during pregnancy. Although AT1-AA often remains elevated up to 8 years postpartum, AT1-AA's effect on CBF autoregulation postpartum is unknown. This study examined whether elevated AT1-AA during pregnancy impairs CBF autoregulation postpartum and if this was augmented by infusion of AT1-AA postpartum. AT1-AA was infused into 12-week-old timed-pregnant Sprague Dawley rats beginning on gestational day 14. Uterine artery resistance index (UARI) was measured on gestational day 18 as a measure of endothelial dysfunction associated with PE. Dams were allowed to deliver. One group was given a second infusion of AT1-AA (50% perinatal dose mimicking levels observed in postpartum PE women) at 9 weeks postpartum. After postpartum week 10, mean arterial pressure (MAP) was measured in conscious rats and CBF autoregulation was measured by laser Doppler flowmetry. AT1-AA during pregnancy increased UARI (P<0.05). AT1-AA during pregnancy did not affect MAP postpartum but did impair CBF autoregulation postpartum. Infusion of AT1-AA postpartum significantly elevated blood pressure (P<0.01) but did not further impair CBF autoregulation. This study demonstrates that circulating AT1-AA during pregnancy causes impairment of CBF autoregulation well into the postpartum period indicating that elevated AT1-AA leads to long-term cerebrovascular consequences. Targeting AT1-AA may prevent cerebrovascular effects associated with PE during pregnancy and postpartum

Placental CD4(+) T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia

AIM: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4(+) T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4(+) T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4(+) T cells from normal pregnant (NP) women. However, the role of PE CD4(+) T cells to cause AT1-AA as a mechanism of hypertension is not known. Our goal was to determine if PE CD4(+) T cells stimulate AT1-AA in pregnant nude-athymic rats. METHODS: CD4(+) T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4(+) T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4(+) T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained. RESULTS: MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4(+) T cells compared to NP nude + NP CD4(+) T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4(+) T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4(+) T cells. CONCLUSIONS: These results show that placental CD4(+) T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy