Abstract 26: CD4+T Cells Play a Critical Role in Mediating Hypertension in Response to Placental Ischemia
Similar to preeclamptic women, hypertension in the chronic reduced uterine perfusion pressure rat model of preeclampsia (RUPP) is associated with increased CD4+ T cell activation, cytokines, sFlt-1 and agonistic autoantibodies to the AngII receptor (AT1-AA). Although we have shown that adoptive transfer of RUPP CD4+ Tcells into normal pregnant (NP) recipients rats causes hypertension and the release of above mentioned factors, the role of endogenous CD4+T cells in mediating the pathophysiology of preeclampsia was unknown. Therefore, we tested the hypothesis that activation of CD4+ T cells causes hypertension and increased sFlt-1, TNF-alpha and AT1-AA. We first examined the effect CD4+ T cell blockade in NP and RUPP rats treated with Orencia, (abatecept, 250mg/kg, infused iv at gestation day 13), clinically used to inhibit T cell activation. RUPP surgical procedure was performed on day 14. On day 19 MAP increased from 94+/-2 mmHg in NP to 123+/-3 mmHg in RUPP control rats. This response was attenuated by CD4+ Tcell blockade, MAP was 104+/-2 mmHg in Orencia treated RUPPs, and 96 +/-2 mmHg Orencia treated NPs. Circulating CD4+ T cells were 66+/-3 in RUPPs compared to 55+/-3 NP rats (p<0.04) but were normalized in Orencia treated RUPP rats (54+/-3). The twofold increase in TNF alpha seen in RUPPs (277+/-47 pg/ml) was decreased to 80 +/-18 pg/ml in Orencia treated RUPPs. Placental sFlt-1 was reduced 70 % to 151+/-28 in Orencia treated RUPP compared 488+/-61 pg/ml in RUPP (P<0.001). AT1-AA decreased from 20+/-0.8 bpm in control RUPP to 6+/-0.7 bpm in Orencia treated RUPPs. We next determined the effect of RUPP in causing hypertension in pregnant T cell deficient rats by examining MAP in NP (121 mmHg) and RUPP athymic nude rats (126 mmHg). In the absence of T cells, hypertension in response to placental ischemia was completely abolished. Collectively these data indicate that activation of CD4+ Tcells in response to placental ischemia plays an important role in the pathophysiology of hypertension associated with preeclampsia.
- © 2012 by American Heart Association, Inc.