CD4+ T Cells Play a Critical Role in Mediating Hypertension in Response to Placental Ischemia

Abstract

Similar to preeclamptic women, hypertension in the chronic Reduced Uterine Perfusion Pressure Rat Model Of Preeclampsia (RUPP) is associated with increased CD4+ T cells, cytokines, sFlt-1 and agonistic autoantibodies to the AngII receptor (AT1-AA). We examined the effect inhibition of T cell co-stimulation in RUPP rats treated with (A) (abatacept, 250 mg/kg, infused i.v. at gestation day 13), on hypertension and sFlt-1, TNF-alpha and AT1-AA. RUPP surgical procedure was performed on day 14. On day 19 MAP increased from 94+2 mmHg in Normal Pregnant (NP) to 123 +/- 3 mmHg in RUPP control rats. This response was attenuated by Abatacept, MAP was 104 +/- 2 mmHg in RUPP +/- A, and 96 +/- 2 mmHg NP +/- A. Percent circulating CD4+ T cells were 66 +/- 3% in RUPPs compared to 55 +/- 3% NP rats (p<0.04) but were normalized in RUPP +/- A rats (54 +/- 3%). The twofold increase in TNF alpha seen in RUPPs (277 +/- 47 pg/ml) was decreased to 80 +/- 18 pg/ml in RUPP+A. Placental sFlt-1 was reduced 70 % to 151 +/- 28 in RUPP +/- A 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 RUPP +/- A. We next determined the effect of RUPP in causing hypertension in pregnant T cell deficient rats by examining MAP in NP (123 +/- 5 mmHg) and RUPP athymic nude rats (123 +/- 7 mmHg). In the absence of T cells, hypertension in response to placental ischemia was completely abolished. Collectively these data indicate that CD4+ Tcells in response to placental ischemia play an important role in the pathophysiology of hypertension associated with preeclampsia.