An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Abstract

The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (T Regs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4 ϩ /CD25ϩ T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 Ϯ 2 mmHg in NP (n ϭ 12) to 127 Ϯ 2 mmHg in RUPP (n ϭ 21) but decreased to 118 Ϯ 2 mmHg in RUPPϩNP TRegs (n ϭ 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-␣ and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 Ϯ 58.7 and 603 Ϯ 88.1 RLU·min Ϫ1 ·mgϪ1 in RUPP and significantly decreased to 178 Ϯ 27.8 and 171 Ϯ 55.6 RLU·min Ϫ1 ·mg Ϫ1 , respectively, in RUPPϩNP TRegs; AT1-AA was 17.81 Ϯ 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 Ϯ 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-␣, and AT 1-AA, which have been shown to increase blood pressure during pregnancy.hypertension; pregnancy; inflammation; oxidative stress; regulatory T cells PREECLAMPSIA IS A PREGNANCY-ASSOCIATED disorder that affects 5-8% of pregnancies and is a major cause of maternal, fetal, and neonatal morbidity and mortality (9,29,37). Hallmark characteristics of preeclampsia are new-onset hypertension after 20 wk gestation, proteinuria, chronic immune activation, fetal growth restriction, and maternal endothelial dysfunction. The pathophysiological mechanisms that lead to the development of preeclampsia are poorly understood. It is thought that poor invasion of trophoblasts leads to insufficient spiral artery remodeling, resulting in placental ischemia (4, 10, 31). The hypoxic environment that results from this placental ischemia is suggested to be an important factor in the development of oxidative stress and a shift in the balance of antiangiogenic and proangiogenic factors, which plays a role in endothelial dysfunction of the placenta and maternal vasculature (10). Previous studies from our laboratory in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia demonstrate that the total population of CD4-positive (CD4 ϩ ) T cells isolated from RUPP spleens and transferred to NP rats causes similar pathology to that seen in RUPP rats (46), demonstrating a role for this population in mediating pathophysiology in response to placental ischemia. Recent data from both clinical and animal model stud...

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

“…Adoptive transfer studies have confirmed that CD4ϩ T-cell function in RUPP rats is altered to promote the production of AT 1 -AA, ET-1, and sFlt-1 in otherwise healthy pregnant rats, as mechanisms of increasing blood pressure during pregnancy (12,49,50). CD4ϩ T-cell population was increased in RUPP compared with NP rats, and TREGs were decreased, consistent with what has been published previously (3,11,14,49,63). Data in the literature have shown that VD reduces proinflammatory CD4ϩ T cells and increases proliferation of TREGs in nonpregnant animals (10,29,31,39).…”

Polymorphisms in interleukin-6 and interleukin-10 may be associated with risk of preeclampsia

“…Previous in vitro and in vivo experimental studies have indicated that IL-10 expression may influence preeclampsia pathogenesis (Medeiros et al, 2014;Cornelius et al, 2015;Wang et al, 2015).…”

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

“…LIGHT, a TNF superfamily member, is also increased in PE and may contribute to placental damage and ischemia (Wang et al, 2014). Plasma levels and CD4 + T cell production of TNF-α are increased in RUPP compared with Norm-Preg rats (LaMarca et al, 2008a; Wallace et al, 2011; Cornelius et al, 2015). Infusion of TNF-α causes HTN and proteinuria during late pregnancy in baboons (Sunderland et al, 2011), rats (Alexander et al, 2002) and mice (Bobek et al, 2015) (Table 5).…”

“…In RUPP rats, the levels of sEng increase in both serum and placenta (Gilbert et al, 2009) while serum TGF-β levels decrease (Cornelius et al, 2015) (Table 4). However, no changes in sEng levels were observed in rat models of HTN-Preg produced by DOCA-salt or L-NAME (Agunanne et al, 2010; Ramesar et al, 2011) (Table 5).…”

“…RUPP rats show increased plasma levels and higher CD4 + T cell production of IL-6 (Wallace et al, 2011; Cornelius et al, 2015), and infusion of IL-6 leads to HTN and proteinuria in pregnant rats (Lamarca et al, 2011). IL-6 may stimulate dimerization of surface receptor GP-130 on ECs leading to abnormal intracellular signaling and vascular dysfunction.…”