Role of Sex Steroids in Modulating Tumor Necrosis

Authors: LaMarca Babbette D Chandler Derrick L Grubbs Lee Bain Jennifer McLemore Gerald R Granger Joey P Ryan Michael J

Publish Date: 2007/11/01

Volume: 20, Issue: 11, Pages: 1216-1221

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Abstract

Babbette D LaMarca Derrick L Chandler Lee Grubbs Jennifer Bain Gerald R McLemore Joey P Granger Michael J Ryan Role of Sex Steroids in Modulating Tumor Necrosis Factor AlphaInduced Changes in Vascular Function and Blood Pressure American Journal of Hypertension Volume 20 Issue 11 November 2007 Pages 1216–1221 https//doiorg/101016/jamjhyper200707002We previously showed that the infusion of tumor necrosis factor alpha TNFα induces hypertension and vascular dysfunction in late pregnant but not virgin rats In the present study we tested the hypothesis that levels of ovarian hormones to mimic pregnancy are required for TNFαinduced changes in vascular function and blood pressure in ratsTwentyonedayrelease pellets containing 17βestradiol progesterone or both were implanted in ovariectomized OVX rats Sham OVX rats were used as controls Twelve days after implantation TNFα or vehicle was infused via osmotic minipumps days 12 to 17 On day 18 mean arterial pressure was measured and animals were sacrificed to assess vascular functionAverage estrogen and progesterone levels across all groups were 106 ± 6 pg/mL and 88 ± 5 ng/mL respectively The level of TNFα was 41 ± 7 pg/mL compared with OVX rats infused with vehicle 4 ± 1 pg/mL The results show that TNFα did not cause elevated mean arterial pressure in OVX rats with increased estrogen progesterone or both Vascular responses to the endotheliumdependent and independent agonists acetylcholine and sodium nitroprusside were also unchanged Phenylephrineinduced contraction was moderately but significantly increased at the highest concentrations 10−4 M only in TNFαinfused ratsThese data suggest that increased ovarian hormones to the levels observed during pregnancy are not sufficient to promote TNFαinduced increases in blood pressure or vascular dysfunction Am J Hypertens 200720 1216–1221 © 2007 American Journal of Hypertension LtdPreeclampsia is defined as newonset hypertension with proteinuria during pregnancy Blood pressure typically increases during the third trimester and remits after delivery of the placenta Increased arterial pressure during preeclampsia is accompanied by elevated circulating inflammatory cytokines such as tumor necrosis factor alpha TNFα interleukin IL1 and IL6 12 Previously our laboratory demonstrated that a twofold increase in circulating TNFα in a normal pregnant rat is sufficient to cause hypertension and increased renal vascular resistance34 Importantly this renal hemodynamic and bloodpressure response occurs only in pregnant but not virgin rats suggesting that placental factors or the hormonal environment of pregnancy may be required for cytokinemediated hypertension during pregnancy in the rat Currently the physiologic mechanisms that facilitate enhanced bloodpressure sensitivity to TNFα during pregnancy are unknown One possible mechanism may be related to the increased circulating levels of sex steroids The role of sex steroids in promoting changes in vascular function and bloodpressure regulation remains a controversial area of investigation The physiologic response to estrogenic hormones varies between animal models vascular beds and concentrations Although a large body of evidence points to a vascularprotective and antihypertensive role for ovarian hormones others suggest a potential proinflammatory role for both estrogens and progestins For example a recent report showed that 17βestradiol facilitates TNFαinduced leukocyte adhesion to endothelial cells by increasing adhesionmolecule expression5 Whether the increase in blood pressure caused by TNFα in pregnant rats requires elevated estrogen and progesterone is not clear To examine this we asked whether the administration of sex steroids estrogen or progesterone to mimic levels observed during pregnancy would be sufficient to promote TNFαinduced hypertension and vascular dysfunction in ovariectomized OVX ratsAll studies were performed in 15weekold OVX SpragueDawley rats purchased from Harlan Inc Indianapolis IN Rats were ovariectomized by Harlan Inc at 12 weeks of age Animals were housed in a temperaturecontrolled room 23°C with a 1212h lightdark cycle Experimental procedures were executed in accordance with the National Institutes of Health guidelines for the use and care of animals All protocols were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical CenterTwentyonedayrelease intradermal pellets of 17βestradiol 05 mg/pellet or progesterone 200 mg/pellet Innovative Research of America Sarasota FL were implanted between the scapulae of OVX rats The target levels of estrogen and progesterone were based on evidence that pregnancy levels are 80 pg/mL and 100 ng/mL respectively6 After 12 days of hormone administration TNFα Biosource International Camarillo CA with heparin or saline with heparin vehicle control was infused intravenously at a rate of 50 ng/day for 5 days days 12 to 17 via miniosmotic pumps model 2001 Alzet Scientific Corp Palo Alto CAMean arterial pressure MAP was measured as previously described34 Briefly rats were catheterized on day 17 with V3 tubing SCI Lake Hayasu City AZ inserted into the carotid artery for bloodsampling and bloodpressure monitoring The catheter was tunneled to the back of the neck and exteriorized after implantation On day 18 rats were placed in individual restraining cages and allowed to acclimate for 1 h Arterial pressure was recorded with a pressure transducer Cobe III Transducer CDX Sema Birmingham AL continuously for 2 h

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