Reduced uterine perfusion pressure T-helper 17 cells cause pathophysiology associated with preeclampsia during pregnancy

Abstract

Preeclampsia is associated with chronic inflammation and an imbalance among T-helper cell subtypes with an increase in T-helper 17 (T17) cells. The objective of this study was to determine a role for T17s, from the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia, in the etiology of hypertension and chronic inflammation during pregnancy. CD4/CD25 T cells were isolated from rat spleens, cultured in T17 media, and were verified as T17s via flow cytometry. On day 12 of gestation, 1×10 T17 cells from RUPP rats were adoptively transferred into NP rats, carotid catheters were inserted on day 18, and on day 19, mean arterial pressure (MAP) was recorded, serum and plasma were collected, and oxidative stress and production of agonistic autoantibodies to the ANG II type I receptor (AT-AA) were analyzed. MAP increased from 100.3 ± 1.7 mmHg in normal pregnant (NP; n = 17) to 124.8 ± 2.1 mmHg in RUPP (n = 22; P < 0.0001) and to 110.8 ± 2.8 mmHg in NP+RUPP T17 (n = 11). Pup weights in NP+RUPP T17s were decreased to 1.92 ± 0.09 g from 2.39 ± 0.14 in NP rats (P < 0.01). AT-AA significantly increased from 0.1 ± 0.2 beats/min in NP to 15.6 ± 0.7 beats/min in NP+RUPP T17s. IL-6 was 22.3 ± 5.7 pg/ml in NP and increased to 60.45 ± 13.8 pg/ml in RUPP (P < 0.05) and 75.9 ± 6.8 pg/ml in NP+RUPP T17 rats (P < 0.01). Placental and renal oxidative stress were 238 ± 27.5 and 411 ± 129.9 relative light units·min·mg in NP and 339 ± 104.6 and 833 ± 331.1 relative light units·min·mg in NP+RUPP T17, respectively. In conclusion, RUPP T17 cells induced intrauterine growth restriction and increased blood pressure, AT-AA, IL-6, and tissue oxidative stress when transferred to NP rats, indicating a role for autoimmune associated T17 cells, to cause much of the pathophysiology associated with preeclampsia.

Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

“…This observation is in line with previous clinical studies demonstrating the ability of NK cells from preeclamptic women to secrete IL-17 [29]. We’ve previously demonstrated that T H 17 cells and IL-17 play a direct role in facilitating IUGR: late gestation blockade of IL-17 signaling with the soluble IL-17 receptor, IL-17 RC, significantly increased both fetal and placental weights in two different models of PE, the RUPP rat and NP + RUPPT H 17s rat [34,35]. In these studies, we did not examine the impact of IL-17 on NK cell proliferation or cytotoxic activation.…”

Immune Cells at the Fetomaternal Interface: How the Microenvironment Modulates Immune Cells To Foster Fetal Development

“…In the reduced uterine perfusion pressure (RUPP) model, reduced uterine artery blood flow is induced by surgical intervention. The preeclampsia-like symptoms induced in this model are T celldependent because T cell-deficient athymic rats are resistant to RUPP-induced hypertension and fetal growth restriction, and disease can be induced by passive transfer of Th17 effector CD4 + T cells (111). The symptoms are mitigated when Treg cells from pregnant control donor rats are administered shortly after the RUPP procedure (112).…”

Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

“…In addition, we have shown that adoptive transfer of RUPP stimulated T H 17 cells into normal pregnant animals induces a preeclamptic phenotype and results in significantly increased cNK cell populations (Cornelius et al. ; Shields et al. ).…”