Novotny Sarah, Wallace Kedra, Herse Florian, Moseley Janae, Darby Marie, Heath Judith, Gill James, Wallukat Gerd, Martin James N, Dechend Ralf, LaMarca Babbette
Department of Obstetrics & Gynecology, University of Mississippi Medical Center, USA.
J Hypertens (Los Angel). 2013 Jun 17;2. doi: 10.4172/2167-1095.1000116.
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-α 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.
与先兆子痫女性相似，子痫前期慢性子宫灌注压降低大鼠模型（RUPP）中的高血压与CD4 T细胞、细胞因子、可溶性血管内皮生长因子受体-1（sFlt-1）以及血管紧张素II受体激动性自身抗体（AT1-AA）增加有关。我们研究了在接受（A）（阿巴西普，250mg/kg，在妊娠第13天静脉输注）治疗的RUPP大鼠中抑制T细胞共刺激对高血压、sFlt-1、肿瘤坏死因子-α（TNF-α）和AT1-AA的影响。RUPP手术于第14天进行。在第19天，正常妊娠（NP）大鼠的平均动脉压（MAP）从94±2mmHg升高至RUPP对照大鼠的123±3mmHg。阿巴西普减弱了这种反应，在接受阿巴西普治疗的RUPP大鼠（RUPP±A）中MAP为104±2mmHg，在接受阿巴西普治疗的NP大鼠（NP±A）中为96±2mmHg。与NP大鼠的55±3%相比，RUPP大鼠循环中CD4 T细胞百分比为66±3%（p<0.04），但在RUPP±A大鼠中恢复正常（54±3%）。RUPP大鼠中观察到的TNF-α两倍升高（277±47pg/ml）在RUPP+A组中降至80±18pg/ml。与RUPP组的488±61pg/ml相比，RUPP±A组胎盘sFlt-1降低70%至151±28（p<0.001）。AT1-AA从对照RUPP组的20±0.8次/分钟降至RUPP±A组的6±0.7次/分钟。接下来，我们通过检测NP大鼠（123±5mmHg）和RUPP无胸腺裸鼠（123±7mmHg）的MAP，确定了RUPP在导致妊娠T细胞缺陷大鼠高血压中的作用。在没有T细胞的情况下，对胎盘缺血的高血压反应完全消除。这些数据共同表明，对胎盘缺血作出反应的CD4 T细胞在子痫前期相关高血压的病理生理学中起重要作用。
