Effects of 17-Hydroxyprogesterone on Tumor Necrosis Factor-α-Induced Hypertension During Pregnancy

Preeclampsia, defined as new-onset hypertension with proteinuria that develops after 20-week gestation, is a multisystem disorder that is estimated to affect 7–10% of pregnant women in the United States.1 The initiating event in preeclampsia is thought to be inadequate trophoblastic invasion into the uterine spiral arteries early in gestation that leads to a reduction in uteroplacental perfusion with the potential for placental ischemia.1,2 Associated with placental ischemia is the widespread dysfunction of the maternal vascular endothelium and the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 (ref. 3). These inflammatory cytokines have been shown to be elevated approximately twofold in women with preeclampsia as well as in placental explants from preeclamptic pregnancies compared to those from normal pregnant women cultured in hypoxic environments.3 TNF-α is an inflammatory cytokine that has been shown to induce structural and functional alterations in endothelial cells.4–6 In normal pregnancy, at physiologic concentrations, TNF-α acts as a regulatory apoptotic agent that limits the invasive abilities of extravillous trophoblastic cells necessary for appropriate placental anchorage and blood flow toward the intervillous space.4 We have shown that continuous low-dose infusion of TNF-α, at a rate that doubles the native cytokine level, increases renal vascular resistance and arterial pressure in pregnant, but not in virgin, rats.7,8 We also previously reported that the increase in arterial pressure and impaired endothelial function in pregnant rats with chronic reductions in uterine perfusion pressure (RUPP) is associated with increased circulating TNF-α and elevated TNF-α transcript in the renal cortex and placenta of RUPP rats compared to normal pregnant rats.9–12 In cultured endothelial cells, cytokines such as TNF-α have been shown to directly increase transcription of the vasoconstrictor peptide endothelin (ET), ET-1 (refs. 5,13). Because endothelial damage is a known stimulus for ET-1 synthesis, increases in the production of ET-1 and activation of ETA receptors have been proposed to participate in the pathophysiology of hypertension during preeclampsia.14,15 Furthermore, plasma concentrations of ET (ET-1) are increased two- to threefold in patients with preeclampsia compared to normal pregnant women. This increase occurs late in the disease process, suggesting that it may play a role in the progression rather than the initiation of preeclampsia.14–18 A role for ET-1 in mediating the pathophysiology induced by placental ischemia has been demonstrated by previous studies performed in our laboratory. In addition to hypertension, increased TNF-α during pregnancy is associated with significant increases in local production of ET-1 in the kidney, placenta, and vasculature.12,19 Furthermore, administration of a selective ETA receptor antagonist attenuates hypertension associated with elevated TNF-α during pregnancy.19 We have recently shown that sequestering endogenous TNF-α produced in response to placental ischemia blunts the increase in tissue ET-1 and arterial pressure in RUPP pregnant rats.12 Collectively these findings support an important role for TNF-α-stimulated ET-1 production in the hypertensive response to placental ischemia during pregnancy. 17-Hydroxyprogesterone is a natural progestin, and in pregnancy increases in the third trimester primarily due to fetal adrenal production. This hormone is primarily produced in the adrenal glands and to some degree in the gonads, specifically the corpus luteum of the ovary. 17-Hydroxy-progesterone caproate (17-OHP) is a synthetic hormone that is similar in structure to 7α-hydroxyprogesterone and also interacts with the progesterone receptor. Progesterone, or specifically 17-OHP, is an agent that has recently made a resurgence in the practice of obstetrics for prevention of recurrent preterm birth in singleton pregnancies.20,21 The anti-inflammatory properties of progesterone are considered to be a mechanism of action. However, research and reports regarding a role for progesterone in the prevention or treatment of preeclampsia are conflicting. Salas et al. suggested that an early rise in maternally derived progesterone might have a pathogenic role in the development of preeclampsia.22 In contrast, a 2005 review by Sammour et al. posited that progesterone is a viable therapeutic agent for the treatment of preeclampsia.23 The focus of our study was therefore to test a potential use for progesterone as an agent for treatment of hypertension in response to elevated TNF-α during pregnancy. The objectives of the study were twofold: first, to determine the effects of progesterone on TNF-α-stimulated ET-1 production, and second to determine the effect of progesterone on attenuating TNF-α-induced hypertension. To achieve these objectives, we first examined ET-1 concentrations from TNF-α-stimulated endothelial cells in the presence and absence of progesterone. Second, we administered 17-OHP to TNF-α-induced hypertensive pregnant rats and analyzed mean arterial pressure and tissue ET-1 production.