209 PROGESTERONE PREVENTS TUMOR NECROSIS FACTOR- INDUCED INCREASES INBLOOD PRESSURE AND THROMBOXANE IN A RAT MODEL OF PREECLAMPSIACHRISTIAN BRIERY (F)1, CARL ROSE1, WALLACE KEDRA1, JAMES MARTIN1,JOEY GRANGER2, WILLIAM BENNETT1, 1University of Mississippi Medical Center,Obstetrics and Gynecology, Jackson, Mississippi, 2University of MississippiMedical Center, Physiology and Biophysics, Jackson, Mississippi

OBJECTIVE: Tumor necrosis factor-a (TNF-a) is elevated in preeclampticwomen and has been shown to induce hypertension and renal dysfunction inpregnant rats. The hormonal environment of pregnancy may contribute toendothelial sensitivity to cytokines during gestation. This study tests thehypothesis that steroid hormones alter the hypertensive response to exogenousTNF-a.

STUDY DESIGN: Virgin Sprague Dawley rats (n=33) were oophorectomizedon day 1. On day 8, rats were randomly assigned to one of the groups: SalineControl, TNF-a alone (50 ng/day), TNF-a plus estrogen (50 ng/day), or TNF-a plus progesterone (50 micrograms/day). Treatments were continuouslyadministered from days 8-14. On day 13, carotid artery catheters wereimplanted for arterial blood pressure. On day 14, animals were placed underanesthesia and serial blood pressures were obtained. Blood samples werecollected and thromboxane (TX) levels measured by a commercially availableELISA system.

RESULTS: TNF-a alone or in combination with estrogen was associatedwith significantly higher blood pressures and circulating levels of TX whencompared with controls. In contrast, there was no difference between controlsand those receiving TNF-a with progesterone on either blood pressure or TXlevels. Kidney weights in the three treatment groups were similar to controls.

CONCLUSION: TNF-a increased both arterial pressure and circulating TXlevels in oophorectomized virgin rats alone or if combined with estrogen.Progesterone temporized the hypertensive response to TNF-a and preventedan increase in TX levels. Future studies are needed to test the hypothesis thatprogesterone supplementation could prevent and/or decrease the hypertensionand endothelial dysfunction associated with human preeclampsia.

210 EXCRETION OF ANGIOGENIC FACTORS IN WOMEN WITH SEVERE PREECLAMPSIA(PE) CATALIN S. BUHIMSCHI (F)1, LISSA MAGLIORE1, EDMUND FUNAI1, ERROLR. NORWITZ1, EDWARD KUCZYNSKI1, RYAN MARTIN1, SUSAN RICHMAN1,SETH GULLER1, CHARLES L. LOCKWOOD1, IRINA A. BUHIMSCHI1, 1Yale University,Obstetrics, Gynecology & Reprod. Sciences, New Haven, Connecticut

OBJECTIVE: Blood and urine concentrations of soluble fms-like tyrosinekinase 1 (sFlt-1), vascular endothelial growth factor (VEGF), and placentalgrowth factor (PlGF) are altered in PE. We sought to identify the relationshipsamong maternal serum concentration of sFlt-1, VEGF and PlGF and theirurinary excretion at the time of disease manifestation.

STUDY DESIGN: Free levels of sFlt-1, VEGF and PlGF were measured byimmunoassay from paired, matched serum-urine samples collected prospec-tively from 64 women in the following groups: non-pregnant reproductive agewomen (NP-CTR n=9), healthy pregnant controls (P-CTR n=13), womenwith mild PE (mPE n=15), and women with severe PE (sPE n=27). Urinaryconcentrations of angiogenic factors were normalized to urinary creatinine andfractional excretions for sFlt-1, VEGF and PlGF calculated. Correlationanalysis between the fractional excretion of each of the angiogenic factors,albuminuria, nonspecific proteinuria and random urine total protein-to-creatinine ratio were also performed.

RESULTS: sFlt-1 serum values were higher in sPE compared with all theother pregnant groups. sPE had significantly lower serum VEGF and PlGFconcentrations. There was no difference in the urinary concentrations ofVEGF among NP-CTR, P-CTR and mPE women. sPE women had more thandouble the urinary VEGF concentration of the mPE group. Fractionalexcretion of VEGF in sPE was significantly increased compared with mPEor P-CTR. sPE women also have increased fractional excretions of sFlt-1 andPlGF. Among sPE women there was no correlation between proteinuria andfractional excretion of VEGF or sFlt-1. There was a significant correlationbetween fractional excretion for PlGF, urinary random total protein/creatinineratio and nonspecific proteinuria.

CONCLUSION: sPE is characterized by increased fractional excretion ofangiogenic factors and especially of VEGF. This derangement is most likelythe result of a complex interaction between local nephrogenous response tohypoxia, alterations in tubular resorption and/or structurally compromisedglomeruli.

211 MATERNAL CIRCULATING TNF&ALPHA LEVELS ARE HIGHLY CORRELATED WITHIL-10 LEVELS, BUT NOT WITH IL-6 AND IL-8 LEVELS, IN WOMEN WITHPREECLAMPSIA. BERNARD J. CANZONERI1, DAVID F. LEWIS1, YANPING ZHANG2,YANG GU1, LISA PHILIBERT3, LYNN J. GROOME1, YUPING WANG2, 1Louisiana StateUniversity Medical Center at Shreveport, Obstetrics and Gynecology, Shreve-port, Louisiana, 2Louisiana State University Health Sciences Center, ObstetricsandGynecology, Shreveport, Louisiana, 3Louisiana StateUniversity, Obstetricsor Gynecology, Shreveport, Louisiana

OBJECTIVE: Maternal cytokine levels of TNF-a, IL-6, IL-8, and IL-10 werereported to be elevated in women with preeclampsia (PE) compared to thosefrom normal pregnancies. The increased cytokine levels are believed tocontribute to the exaggerated inflammatory response and endothelial dysfunc-tion in PE. The purpose of the study was to determine whether these cytokinelevels are correlated in PE.

STUDY DESIGN: Venous blood was obtained from 50 women diagnosedwith PE at the time of admission and within 24 hours post delivery. Thecriteria for PE are followed by ACOG guidelines. Plasma concentrations forTNF-a, IL-6, IL-8, and IL-10 were measured by ELISA. Data are presented asmeanG SE and analyzed by paired t-test. Correlations between cytokine levelsand the levels with maternal blood pressure (Bp) were analyzed by simplelinear regression and correlation. A p level less than 0.05 is set for statisticallydifferent.

RESULTS: 1) There were no statistical differences for the plasma levels ofTNF-a, IL-6, IL-8, and IL-10 before and within 24 hours after delivery, TNF-a: 135.08G30.09 vs. 120.74G30.33 pg/ml; IL-6: 17.99G6.35 vs. 21.01G3.12pg/ml; IL-8: 6.63G1.78 vs. 6.24G1.60 pg/ml; and IL-10 310.58G127.37 vs.259.54G109.65 pg/ml, pO0.05, respectively. 2) TNF-a and IL-10, but not IL-6and IL-8, levels were significantly correlated before and 24 hours after delivery:TNF-a: y=19.963C0.953*x; r2=0.924; IL-10: y=10.521C1.113*x;r2=0.984, p!0.001, respectively. Furthermore, TNF-a levels were correlatedwith IL-10 levels, but not with IL-6 and IL-8 levels, before:y=24.606C0.339*x; r2=0.842, and after: y=18.281C0.366*x; r2=0.888,p!0.001, respectively. 3) The mean maternal Bp was 164G3/104G2 mmHg.No correlation was found between these cytokine levels and maternal Bp.

CONCLUSION: The correlation patterns of TNF-a with IL-10 and TNF-awith IL-6 and IL-8 suggest that disparity functional regulations for thesecytokines exist in the maternal circulation in PE.

212 ANTIHYPERTENSIVE THERAPY IS ASSOCIATED WITH AN ATTENUATED RISEIN SFLT-1 DURING PREGNANCY DARCY CARR1, LAN TRAN1, DEBRA BRATENG1,JANE SHOFER2, S ANANTH KARUMANCHI3, THOMAS EASTERLING1, 1University ofWashington, Obstetrics & Gynecology, Seattle, Washington, 2University ofWashington, Rehab Research & Development, Seattle, Washington, 3BethIsrael Deaconess Medical Center, Renal Division, Boston, Massachusetts

OBJECTIVE: A hyperdynamic circulation (high cardiac output, CO) is acharacteristic of the preclinical phase of preeclampsia (PreE). We previouslydemonstrated that treating the high CO with atenolol decreases the risk ofPreE. The antiangiogenic molecule sFlt-1 is also increased prior to the clinicaldisease. We hypothesized that hemodynamically directed therapy to decreaseCO would blunt the rise in sFlt-1 levels. We evaluated this hypothesis bycomparing sFlt-1 levels between women with high CO who were treated withatenolol and controls.

STUDY DESIGN: CO, mean arterial pressure (MAP), and plasma sFlt-1 levels were measured at enrollment and at 6-8 week intervals duringpregnancy in: 1) a group with clinical risk factors for PreE (high-risk, HR)treated with atenolol for high CO (O7.4 L/min), and 2) a low-risk group nottreated (control). Longitudinal data were analyzed by generalized estimatingequations.

RESULTS: 46 were in the HR treated group and 25 in the control group.There were no differences in maternal age (meanGSEM: 28.3G0.8 vs30.3G1.1 years), enrollment gestational age (17.3G0.6 vs 16.1G0.8 weeks),and proportion of primigravidas (50 vs 72%). Baseline CO (9.7G.2 vs 7.3G.3L/min, P!0.001) and MAP (91.8G1.6 vs 79.6G1.5 mmHg, P!0.001) werehigher in the HR group. CO and MAP decreased during pregnancy in the HRtreated group compared to controls (P!0.001 for both). The rise in sFlt-1 during pregnancy was attenuated in the HR treated group compared tocontrols (P!0.001). A subgroup analysis between the HR treated group andcontrols with a similar hemodynamic abnormality (COO7.4 L/min; n=11)also demonstrated a steeper rise in sFlt-1 in the high CO controls compared tothe HR treated group (P!0.002).

CONCLUSION: Hemodynamically directed antihypertensive therapy inwomen with risk factors for PreE significantly blunts the rise in sFlt-1,suggesting a concordant effect of treatment on hemodynamics and angiogenicfactors. Thus, hemodynamically directed therapy in high risk pregnanciesimproves the angiogenic factors associated with the endothelial dysfunction ofPreE.

S70 SMFM Abstracts