Wallace Kedra, Novotny Sarah, Heath Judith, Moseley Janae, Martin James N, Owens Michelle Y, LaMarca Babbette
Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Am J Physiol Regul Integr Comp Physiol. 2012 Jul 15;303(2):R144-9. doi: 10.1152/ajpregu.00049.2012. Epub 2012 May 30.
We have shown that adoptive transfer of CD4(+) T cells from placental ischemia (reduction in uteroplacental perfusion, RUPP) rats causes hypertension and elevated inflammatory cytokines during pregnancy. In this study we tested the hypothesis that adoptive transfer of RUPP CD4(+) T cells was associated with endothelin-1 activation as a mechanism to increase blood pressure during pregnancy. CD4(+) T cells from RUPP or normal pregnant (NP) rats were adoptively transferred into NP rats on gestational day 13. Mean arterial pressure (MAP) was analyzed on gestational day 19, and tissues were collected for endothelin-1 analysis. MAP increased in placental ischemic RUPP rats versus NP rats (124.1 ± 3 vs. 96.2 ± 3 mmHg; P = 0.0001) and increased in NP recipients of RUPP CD4(+) T cells (117.8 ± 2 mmHg; P = 0.001 compared with NP). Adoptive transfer of RUPP CD4(+) T cells increased placental preproendothelin-1 mRNA 2.1-fold compared with NP CD4(+) T cell rats and 1.7-fold compared with NP. Endothelin-1 secretion from endothelial cells exposed to NP rat serum was 52.2 ± 1.9 pg·mg(-1)·ml(-1), 77.5 ± 4.3 pg·mg(-1)·ml(-1) with RUPP rat serum (P = 0.0003); 47.2 ± .16 pg·mg(-1)·ml(-1) with NP+NP CD4(+) T cell serum, and 62.2 ± 2.1 pg·mg(-1)·ml(-1) with NP+RUPP CD4(+) T cell serum (P = 0.002). To test the role of endothelin-1 in RUPP CD4(+) T cell-induced hypertension, pregnant rats were treated with an endothelin A (ET(A)) receptor antagonist (ABT-627, 5 mg/kg) via drinking water. MAP was 92 ± 2 mmHg in NP+ET(A) blockade and 108 ± 3 mmHg in RUPP+ET(A) blockade; 95 ± 5 mmHg in NP+NP CD4(+) T cells+ET(A) blockade and 102 ± 2 mmHg in NP+RUPP CD4(+) T cells+ET(A) blockade. These data indicate the importance of endothelin-1 activation to cause hypertension via chronic exposure to activated CD4(+) T cells in response to placental ischemia.
我们已经表明，从胎盘缺血（子宫胎盘灌注减少，RUPP）大鼠体内过继转移CD4(+) T细胞会导致妊娠期间高血压和炎性细胞因子升高。在本研究中，我们检验了这样一个假设：RUPP CD4(+) T细胞的过继转移与内皮素-1激活相关，这是妊娠期间血压升高的一种机制。在妊娠第13天，将来自RUPP或正常妊娠（NP）大鼠的CD4(+) T细胞过继转移到NP大鼠体内。在妊娠第19天分析平均动脉压（MAP），并收集组织进行内皮素-1分析。与NP大鼠相比，胎盘缺血RUPP大鼠的MAP升高（124.1±3 vs. 96.2±3 mmHg；P = 0.0001），并且在接受RUPP CD4(+) T细胞的NP受体中MAP也升高（117.8±2 mmHg；与NP相比P = 0.001）。与NP CD4(+) T细胞大鼠相比，RUPP CD4(+) T细胞的过继转移使胎盘前内皮素原-1 mRNA增加2.1倍，与NP相比增加1.7倍。暴露于NP大鼠血清的内皮细胞分泌的内皮素-1为52.2±1.9 pg·mg(-1)·ml(-1)，暴露于RUPP大鼠血清时为77.5±4.3 pg·mg(-1)·ml(-1)（P = 0.0003）；暴露于NP+NP CD4(+) T细胞血清时为47.2±0.16 pg·mg(-1)·ml(-1)，暴露于NP+RUPP CD4(+) T细胞血清时为62.2±2.1 pg·mg(-1)·ml(-1)（P = 0.002）。为了检验内皮素-1在RUPP CD4(+) T细胞诱导的高血压中的作用，通过饮用水给妊娠大鼠施用内皮素A（ET(A)）受体拮抗剂（ABT-627，5 mg/kg）。在NP+ET(A)阻断组中MAP为92±2 mmHg，在RUPP+ET(A)阻断组中为108±3 mmHg；在NP+NP CD4(+) T细胞+ET(A)阻断组中为95±5 mmHg，在NP+RUPP CD4(+) T细胞+ET(A)阻断组中为102±2 mmHg。这些数据表明，内皮素-1激活对于因胎盘缺血而长期暴露于活化的CD4(+) T细胞导致高血压具有重要意义。
