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. Author manuscript; available in PMC: 2010 Jan 25.
Published in final edited form as: Am J Hypertens. 2009 Sep 10;22(10):1120–1125. doi: 10.1038/ajh.2009.149

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

Sharon D Keiser 1,2, Edward W Veillon 1,2, Marc R Parrish 1,2, William Bennett 1,2, Kathy Cockrell 1,2, Lillian Fournier 1,2, Joey P Granger 1,2, James N Martin Jr 1,2, Babbette Lamarca 1,2
PMCID: PMC2810643  NIHMSID: NIHMS162581  PMID: 19745821

Abstract

BACKGROUND

Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) may be an important link between placental ischemia and hypertension in preeclampsia. We examined the effect of 17-hydroxyprogesterone caproate (17-OHP) on TNF-α-stimulated endothelin (ET) production and hypertension during pregnancy.

METHODS

TNF-α-stimulated ET was examined from endothelial cells cultured in the presence and absence of progesterone. Blood pressure and tissue ET-1 were measured in the following groups of pregnant rats: controls, 17-OHP (3.32 mg/kg), TNF-α treated (50 ng/day), TNF-α treated+17-OHP.

RESULTS

Progesterone abolished TNF-α-stimulated ET-1 from endothelial cells. TNF-α-induced hypertension was associated with significant increases in renal and placental ET-1. Administration of 17-OHP attenuated TNF-α-induced hypertension and decreased renal ET-1.

CONCLUSION

Progesterone directly abolished TNF-α-stimulated ET-1 and attenuated TNF-α-induced hypertension, possibly via suppression of the renal ET-1 system. These data suggest that treatment with progesterone of hypertension associated with elevated cytokines during pregnancy may be worthy of further consideration.

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.

METHODS

In vitro experimental protocols

To determine the direct effects of progesterone on TNF-α-induced ET synthesis, we examined the effect of progesterone on TNF-α-stimulated endothelial cells in culture. The dose-dependent response to recombinant human TNF-α on ET-1 production was examined in human umbilical venous endothelial cells (HUVECs; ATCC, Manassas, VA) using 0.01, 0.10, 1.0, and 10.0 ng TNF-α added per ml of serum-free culture media. The dose-dependent (0.01, 0.10, 1.0, and 10 ng/ml) effects of TNF-α on ET-1 production were also examined in the presence of cell culture grade progesterone (50 ng/ml) (Sigma Chemicals, St Louis, MO). This level is comparable to circulating progesterone in pregnant women. Following an 8-h experimental incubation, cell culture supernatant was removed and used for ET-1 measurements.

Endothelial cell culture

Human umbilical venous endothelial cells, HUVEC, passage 2, were used for all experiments. Culture media was 50%/50% Dulbecco’s modified Eagle’s medium/Medium 199 (Gibco, Billings, MT) with 10% fetal bovine serum (Hyclone, Logan, UT) and 10 ml antimycotic–antibiotic (Gibco) at 37 °C in a humidified atmosphere of 5% CO2–20% O2–75% N2. Seventy percent confluent monolayers were incubated for 48 h in serum-free media before TNF-α/progesterone exposure.

Determination of ET-1

One milliliter of cell culture media was extracted from the flask before cell harvesting and used to determine concentrations of excreted ET-1. Levels were determined by enzyme-linked immunosorbent assay, specifically with the Parameter human ET, ET-1, from R&D Systems (Minneapolis, MN). Assays were performed following instructions outlined in the manual provided with the kit from R&D Systems.

Protein isolation and quantitation

Total protein was isolated and used to standardize immunoassay results. After trypsinization, cells were collected by centrifugation, washed with 200 µl Dulbecco’s phosphate-buffered saline and centrifuged. A volume of 200 µl of protein lysis buffer was added and cells were disrupted by vortexing. The lysate was placed on ice for 5 min and cell debris was collected by centrifugation for 2 min. The protein lysate was extracted and placed in a clean tube. One microliter was mixed with 800 µl water and 199 µl BioRad protein assay solution. Concentrations were measured spectrophotometrically at 595 nm.

In vivo experimental design

All studies were performed in timed-pregnant Sprague-Dawley rats purchased from Harlan Sprague Dawley (Indianapolis, IN). Animals were housed in a temperature-controlled room (23 °C) with a 12:12-h light/dark cycle. All experimental procedures executed in this study were in accordance with National Institutes of Health guidelines for use and care of animals, and the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center approved all protocols.

Experiments were performed in the following four groups of pregnant rats: controls (n = 4), controls+17-OHP (n = 4), TNF-α treated (n = 9), and TNF-α treated+17-OHP (n = 5). On day 14 of gestation, all rats were anesthetized with 2% isoflurane (W.A. Butler, Dublin, OH) delivered by an anesthesia apparatus (Vaporizer for Forane Anesthetic; Ohio Medical Products, Gurnee, IL). The controls underwent an abdominal examination under anesthesia to confirm pregnancy. The 17-OHP (Marty’s Compounding Pharmacy, Jackson, MS) was diluted in normal saline and administered intraperitoneally as 0.5 cm3 solution of 3.32 mg/kg 17-OHP to pregnant rats. We chose the one-time 17-OHP dose to be the weight equivalent of a typical human dose for the prevention of preterm labor. The control rats receiving 17-OHP were similarly anesthetized on day 14, and 17-OHP was then delivered via sterile syringe through a 1–2 cm incision into the peritoneal cavity. TNF-α-treated pregnant rats underwent intraperitoneal insertion of a mini-osmotic pump containing TNF-α on day 14 of gestation. Recombinant, purified rat TNF-α (50 ng/day; BioSource International, Morrisville, NC) was infused continuously for 5 days, from day 14–19 of gestation, using the mini-osmotic pump. The dose of TNF-α used is the standard dose shown previously to consistently produce a twofold increase in the circulating level of TNF-α. In the TNF-α+17-OHP group, the 17-OHP was administered immediately following insertion of the mini-osmotic pump infusing TNF-α and before closure of the incision.

On day 18 of gestation, all rats were surgically instrumented with a carotid artery catheter for subsequent arterial pressure measurement. Carotid artery catheters were placed under isoflurane anesthesia. A catheter of V-3 tubing (SCI, Lake Hayasu City, AZ) was inserted into the carotid artery and the catheter was tunneled to the back of the neck and exteriorized after implantation. On day 19 of gestation, mean arterial pressures were recorded in conscious rats; pups and placentas were counted and weighed and blood samples and kidneys were collected for molecular analysis.

Arterial pressure was measured by placing the pregnant rats into individual restraining cages. Arterial pressure was monitored with a pressure transducer (COBE III Transducer; CDX Sema, Birmingham, AL) connected to the carotid artery catheter and was recorded continuously for a 10-min period following 1-h stabilization. Rats were then anesthetized using isoflurane for blood and tissue collection.

RNA isolation and analysis of tissue ET-1

The renal cortex and medulla were separated immediately after harvesting and quickly frozen in liquid nitrogen and stored at −80 °C. Placentas were collected and quickly frozen in liquid nitrogen and stored at −80 °C. Total RNA was extracted using the RNeasy kit (Qiagen, Valencia, CA) after the tissue was crushed in liquid nitrogen with a mortar and pestle. Isolation procedure was then performed as outlined in the instructions provided by the manufacturer.

Genomic DNA was digested with DNase1 following instructions outlined by Ambion. RNA was quantified spectrophotometrically using an eppendorf (BioPhotometer, Hamburg, Germany). cDNA was synthesized from 1 µg of RNA with BioRad Iscript cDNA reverse transcriptase (BioRad), and real-time PCR was performed using the BioRad Syber Green supermix and iCycler (BioRad) as described previously.12 Levels of mRNA expression were calculated using the mathematical formula for the mean normalized cycle threshold (Δ/ΔCT) recommended by Applied Biosystems (Applied Biosystems User Bulletin, no. 2, 1997).

Determination of serum TNF-α levels

A rat TNF-α colorimetric sandwich ELISA (R&D Systems) was used for quantification of serum TNF-α levels between 12.5 and 800 pg/ml. This assay displayed a sensitivity level of 5 pg/ml and interassay variability of 10% and intra-assay variability of 5.1%.

Determination of plasma progesterone levels

Plasma progesterone was determined using a progesterone ELISA from Oxford Biomedicals Research (Oxford, MI). This test kit operates on the basis of competition between the enzyme conjugate and the progesterone in the sample for a limited number of binding sites on the antibody coated plate. The assay is used for quantification of progesterone levels between 0.1 and 100 ng/ml.

Statistical analysis

All values are reported as mean ± s.e.m. Difference between control and experimental groups were analyzed using analysis of variance with Tukey–Kramer multiple comparison test. Data were considered statistically significant at P values <0.05. Statistical analysis of real-time PCR results was performed using the Δ/ΔCT values and standard deviations analyzed by one-way analysis of variance and Tukey–Kramer multiple comparison test.

RESULTS

Effects of progesterone on TNF-α-induced ET-1

The dose-dependent (0.01, 0.10, 1.0, and 10 ng/ml) effects of TNF-α on ET production by human umbilical vein endothelial cells are shown in Figure 1. ET-1 production in response to TNF-α increased significantly at TNF-α concentrations of 1.0 and 10 ng/ml. ET-1 production increased by 60% or from 7.94 ± 0.4 to a maximal concentration of 13.3 ± 1.6 pg/ml at a dose of 10 ng/ml.

Figure 1.

Figure 1

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The effect of TNF-α on endothelin (ET-1) production in control human umbilical vein endothelial cells (HUVECs) and progesterone-treated tumor necrosis factor-α (TNF-α)–induced activation of HUVECs. *P < 0.05 vs. baseline; †P < 0.05 vs. control.

In the presence of progesterone, basal ET-1 production is significantly decreased. In addition the dose-dependent (0.01, 0.10, 1.0, and 10 ng/ml) effects of TNF-α on ET-1 production are attenuated in the presence of progesterone, as illustrated in Figure 1.

Administration of 17-OHP attenuated TNF-α-induced hypertension

Pregnant control rats had a MAP of 97 ± 2 mm Hg. Pregnant rats given 17-OHP alone had a MAP of 98 ± 3 mm Hg. MAP increased with TNF-α administration to 115 ± 3 mm Hg (P < 0.01 vs. nonpregnant), however, was only 100 ± 4 mm Hg in TNF-α-induced hypertensive rats administered 17-OHP (P < 0.01 vs. TNF-α alone) as shown in Figure 2a.

Figure 2.

Figure 2

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(a) Mean arterial pressure, (b) circulating tumor necrosis factor-α (TNF-α) (pg/ml), (c) plasma progesterone in control pregnant rats, TNF-α-induced hypertensive pregnant rats, control pregnant rats treated with 17-hydroxyprogesterone caproate (17-OHP), and TNF-α+17-OHP at day 19 of gestation. *P < 0.05 vs. control pregnant rats; †P < 0.05 vs. TNF-α-induced hypertensive pregnant rats. (c) *P < 0.02 TNF-α-induced hypertensive pregnant rats vs. TNF-α+17-OHP. All data are expressed as mean ± s.e.m.

Pup weights did not differ among the groups. Pups from normal pregnant rats weighed 2.1 ± 0.9 g. Pups from TNF-α induced hypertensive pregnant rats weighed 2.3 ± 0.3 g. Pups from rats receiving 17-OHP alone weighed 2.1 ± 0.6 g and weighed 2.2 ± 0.3 g from TNF-α+17-OHP rats.

TNF-α levels in control and 17-OHP treated pregnant rats

Figure 2b illustrates the twofold increase in circulating TNF-α achieved when comparing nonpregnant with TNF infused rats, 23 ± 7 vs. 47 ± 6 pg/ml, respectively. TNF-α levels in the 17-OHP treated group increased from 16 ± 7 pg/ml in 17-OHP controls to 39 ± 10 pg/ml TNF-α+17-OHP.

Progesterone levels in control and 17-OHP treated pregnant rats

Figure 2c illustrates the levels of plasma progesterone determined in the study. Progesterone levels in control normal pregnant rats was 24 ± 3.5 ng/ml. Administration of 17-OHP to normal pregnant rats did not increase basal plasma progesterone levels (22 ± 2.6 ng/ml). Interestingly, plasma progesterone was significantly decreased to 15 ± 1.5 ng/ml (P < 0.002) by administration of TNF-α to normal pregnant rats. Although administration of 17-OHP to control rats did not increase basal levels in the 17-OHP treated group, injection of 17-OHP returned plasma progesterone levels in the TNF-α-treated group to normal baseline concentrations (23 ± 2.1 ng/ml).

Effect of TNF-α and 17-OHP on local production of tissue ET-1

Consistent with previous studies, prepro-ET (ppET-1) mRNA levels significantly increased in the renal cortices of TNF-α-induced hypertensive pregnant rats (5.2 ± 0.9 relative units P < 0.05). However, ppET-1 increased to only 3.2 ± 1 relative units in TNF-α+17-OHP treated pregnant rats (Figure 3). Although the difference in ppET-1 in response to 17-OHP in the TNF-α-treated groups was not significantly altered, the blunted response could have contributed to, albeit was not fully responsible for, the blood pressure difference observed in the study.

Figure 3.

Figure 3

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Preproendothelin levels in the (a) renal cortex and (b) placental tissues of RNA isolated from control pregnant rats, tumor necrosis factor-α (TNF-α)–induced hypertensive pregnant rats (P < 0.02), and TNF-α-treated+17-hydroxyprogesterone caproate (17-OHP) pregnant rats. All data are expressed as mean ± s.e.m. (*P < 0.02 TNF-α vs. nonpregnant).

We have previously shown that placental ppET-1 increases during TNF-α-induced hypertension. Consistent with our previous work, ppET-1 increased significantly in the placental tissues of TNF-α-induced hypertensive pregnant rats (7.6 ± 1 relative units; Figure 3) but remained unchanged in the 17-OHP treated TNF-α-infused pregnant rats (7.4 ± 1 relative units).

Comment

The pathophysiologic processes that underlie preeclampsia have been proposed to occur in two stages: stage 1, reduced placental perfusion, and stage 2, the maternal clinical syndrome.1,2 Placental ischemia/hypoxia is believed to result in the release of a variety of placental factors that have profound effects on blood flow and arterial pressure regulation.1,2,9,10 To date, there are no effective prevention or treatment strategies for women with this disease, except for early delivery of the fetus and placenta. The focus of our study was to test a potential use for progesterone, 17-OHP, an anti-inflammatory agent that has been reintroduced to the obstetric practice for the prevention of preterm labor of singleton pregnancies, for treatment of hypertension associated with increased inflammatory cytokines such as TNF-α during pregnancy.

TNF-α is elevated in preeclamptic women and has been implicated in the disease process.5 We have previously reported that chronic infusion of TNF-α in pregnant rats significantly increases blood pressure and local production of ET-1 in the kidney, placenta, and vasculature.19 The increase in mean arterial pressure in response to TNF-α is completely abolished in pregnant rats treated with an ETA receptor antagonist.19 Collectively, these findings suggest that ET, via ETA receptor activation, plays an important role in mediating the hypertension produced by chronic RUPP as well as TNF-α-induced hypertension in pregnant rats.

This study was designed to test the efficacy of progesterone as an antihypertensive treatment during TNF-α-induced hypertension mediated via activation of the ET-1 system. TNF-α regulates ET-1 production at the transcriptional level by activation of the fos/jun pathway.5 In this study, we demonstrated that progesterone directly attenuates basal ET-1 production from endothelial cells in culture. Under control conditions, we found that TNF-α caused a dose-dependent increase in ET-1 production in human umbilical vein endothelial cells, reaching a maximal twofold effect at a TNF-α concentration of 1 ng/ml. Our dose-dependent effects of TNF-α on ET-1 production from HUVECs were very similar to the effects in bovine aortic endothelial cells reported by Marsden and Brenner.5 The addition of progesterone attenuated the dose-dependent effects of TNF-α on ET-1 production. Thus, our in vitro findings indicate that progesterone has an important direct effect on endothelial cells to blunt TNF-α-stimulated ET-1 synthesis.

In addition, we found that administration of 17-OHP (at a dose delivered to prevent preterm labor in pregnant women) to TNF-α-induced hypertensive pregnant rats decreased arterial pressure in response to TNF-α during pregnancy. Importantly, we found no differences in pup weight of rats receiving 17-OHP compared to normal pregnant rats, indicating that the potential antihypertensive effect of 17-OHP was not deleterious to the fetus. As with our previous studies, we found that TNF-α-induced hypertension is associated with increased ET-1 transcript in both renal cortical and placental tissues. Administration of 17-OHP had no effect on placental ET-1 transcript but blunted the significant increase in ppET-1 in the renal cortices of TNF-α-induced hypertensive pregnant rats. In a previous study performed in our laboratory we administered 17-OHP to the placental ischemic RUPP rat model.24 In this study, Veillion et al. demonstrated that administration of 17-OHP markedly decreased circulating TNF-α and IL-6 in response to placental ischemia. Furthermore, we demonstrated that administration of 17-OHP to RUPP rats decreased transcription of ET-1 in the renal cortices, thus suggesting one possible mechanism for the decrease in arterial pressure. However, similar to the findings in this study, administration of 17-OHP had no effect on ET-1 in placentas of RUPP rats, thus illustrating the importance of other factors released in the ischemic placenta that may activate the ET system during pregnancy.24 We have previously demonstrated that placental ischemia is also associated with increases in the soluble antagonist of vascular endothelial growth factor (sFlt-1), agonistic autoantibodies to the angiotensin type 1 receptor (AT1-α A), as well as with decreases in nitric oxide availability.25 Although these factors could play a role in ET-1 in the placenta and may contribute to the remaining increase in blood pressure in the RUPP rats treated with 17-OHP, they were not further evaluated.

In addition, we have previously demonstrated these factors, such as AT1-α A to be produced in response to TNF-α-induced hypertension in pregnant rats.25 We are currently investigating the role of TNF-α to induce sFlt-1 production during pregnancy. Although other inflammatory cytokines, nitric oxide, sFlt-1, or AT1-α As were not determined in this study, it is possible that the anti-inflammatory effects of 17-OHP affected their production and could therefore be one mechanism for the attenuation of the hypertension in response to TNF-α during pregnancy. Studies are designed in which these factors will be the subject of further investigation into the role of 17-OHP as possible antihypertensive therapy in the setting of placental ischemia.

Although our findings illustrate the antihypertensive effects of 17-OHP via blunting of TNF-α-stimulated ET-1 synthesis both in vitro and in vivo during pregnancy, they do not quantify the importance of varying concentrations of progesterone between preeclamptic vs. normal pregnant women. Furthermore, additional pathways activated by TNF-α were not measured in response to 17-OHP and could be playing a key role in attenuating hypertension in response to TNF-α. Future studies investigating the potential vasodilatory, antihypertensive, and anti-inflammatory actions of 17-OHP are necessary to define the potential use of this medication in treating hypertension during pregnancy. Our laboratory is currently examining the underlying differences in endogenous progesterone levels among preeclamptic women vs. women with normal pregnancies. Not until well-controlled clinical trials examining a potential protective role for 17-OHP, either as an anti-inflammatory or antihypertensive agent, during preeclampsia are executed, will we define the role of 17-OHP as a potential therapeutic agent for women with this disease.

Footnotes

Disclosure: The authors have no conflicts of interest to disclose.

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