SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018 - 308A

308A

Reproductive Sciences Vol. 25, Supplement 1, March 2018

METHODS: Omental resistance arteries (OAs; <400µM) from women
with NP or PE were assessed ex vivo by wire myography. (1) Doseresponse curves to U46619 (10-10-10-5.7M) were constructed for OAs
from women with PE pre- and post-treatment with Kyn (1-6mM; 1hr) or
vehicle diluent. (2) Dose-response curves to Kyn (0.05-3mM) or vehicle
diluent were constructed for pre-constricted arteries (U46619, EC80)
in the presence or absence of specific inhibitors of large-conductance
calcium-activated potassium channels (BKca channels; Paxilline 1µM
or Iberiotoxin 100nM).
RESULTS: In OAs from women with PE (N=7), U46619 EC50 (dose
required for half-maximal constriction) was significantly increased
following 1hr treatment with Kyn 1mM (paired T-test, p=0.004), 3mM
(p=0.02) or 6mM (p=0.003) but not vehicle (control). Kyn induced
vasorelaxation of OAs obtained from women with PE (N=9; 2-way
ANOVA, p=0.03; remaining constriction: control 0.65 ±0.05 vs. Kyn 0.41
±0.08) and NP (N=9; p=0.03; control 0.70 ±0.07 vs. Kyn 0.34 ±0.09).
This effect was inhibited by BKca channel inhibition with Paxilline in both
PE (N=8, p<0.01) and NP (N=8, p=0.04); in NP this was validated with
a second BKca inhibitor Iberiotoxin (N=5, p=0.01).
CONCLUSION: Kyn reduces vasopressor sensitivity and causes
vasorelaxation in systemic arteries of women with PE. This suggests
Kyn may offer a new strategy to bypass the dysfunctional endothelium
to attenuate maternal hypertension in PE. In arteries from NP and PE,
Kyn-induced relaxation is mediated via BKca channels, a previously
unreported mechanism of action for Kyn.

S-170
AT2 Receptor Activation Restores Vascular Function in Preeclamptic
Vessels and Blood Pressure in Hypertensive Rat Pregnancies. Jay S
Mishra†, Sathish Kumar*. University of Wisconsin-Madison, Madison,
WI, United States.
INTRODUCTION: Despite multiple studies, the mechanisms that
lead to normal and abnormal gestational vascular adaptions are not
fully understood. During normal pregnancy, the pressor responses to
angiotensin II is blunted. We have shown that this gestational vascular
blunting to angiotensin II is because of dramatic increase (~ 6-8-fold) in
expression of vasodilatory angiotensin type 2 receptor (AT2R). In this
study we hypothesized that the vasodilatory AT2R expression is down
regulated in preeclamptic pregnancies and rat models of gestational
hypertension and that upregulation and activation of AT2R would restore
BP.
METHODS: Placenta were collected from cesarean delivered, 30-38
week normotensive and preeclamptic pregnant women. Placental vessels
and explants were ex vivo incubated with and without AT2R agonist C21
(100 nM) for 24 hours, and the tissues were then processed to determine
AT1R and AT2R expression and sFlt-1 and VEGF production. Gestational
hypertensive rats (induced with s-Flt-1 or testosterone propionate) were
treated with and without AT2R agonist C21 (1 mg/kg/day, oral gavage)
for 5 days from gestational day (GD) 15 to 20 and changes in mesenteric
vascular AT2R expression and BP (through telemetry) were measured.
RESULTS: AT2R expression was reduced while AT1R expression was
increased (5-fold ↑ in AT1R/AT2R ratio) in preeclamptic vessels compared
to normotensive pregnancies. AT2R agonist C21 treatment restored AT1R/
AT2R ratio by increasing AT2R expression and decreasing AT1R expression
in preeclamptic vessels but did not have any effect in normotensive vessels.
The production of sFlt-1 was 2-fold higher and VEGF was 50% lower in
preeclamptic explants and this was restored to normotensive levels by C21
treatment. AT2R expression in mesenteric arteries was reduced and BP was
higher in gestational hypertensive rats. Treatment with C21 upregulated
AT2R expression and restored BP in hypertensive rats to normal pregnant
levels. Administration of C21 to normal control pregnant rats did not
alter AT2R expression and BP. Thus, AT2R activation upregulated its own
receptor restoring AT1R/AT2R and sFlt-1/VEGF balance in preeclamptic
vessels and restored BP in gestational hypertensive rat models.
CONCLUSION: Decreased expression and function of vasodilatory
AT2R during preeclampsia may favor angiotensin II acting on the
vasoconstrictive AT1R and contributing for inappropriate RAS activation

Scientific Abstracts

and hypertension. Strategies that counter inappropriate RAS activation
through use of AT2R agonists may be a new class of drugs for controlling
gestational vascular dysfunction and hypertension.

S-171
Uric Acid Levels and Their Association with Preeclampsia, Birth
Weight, and Placental Underperfusion. Carole A McBride, Ira M
Bernstein*. University of Vermont College of Medicine, Burlington, VT,
United States.
INTRODUCTION: Hyperuricemia is frequently observed with
preeclampsia, and elevated serum uric acid concentrations are associated
with decreased birth weight. We explored the relationship between uric
acid levels prior to and during pregnancy, and their association with body
composition, markers of inflammation, birth weight, preeclampsia, and
placental underperfusion.
METHODS: One hundred birth outcomes were analyzed from a
prospective study in which women were evaluated prior to pregnancy
and at 30-32 weeks of pregnancy (late pregnancy). Uric acid levels from
each visit were compared with measures of insulin resistance (HOMA-IR)
and C-reactive protein concentrations (CRP). The relationship between
pre-pregnancy body composition, as measured with DEXA, with uric acid
was examined. Medical records were reviewed for pregnancy outcome.
Placentas were obtained and scored for placental underperfusion (y/n)
at the time of birth. Associations between uric acid levels and change
between visits were evaluated for their relationship with birth weight
percentile (BW%), preeclampsia, and placental underperfusion.
RESULTS: There were no associations of uric acid with age, parity, or
cycle day of study. Uric acid levels were associated with increased body
mass index (BMI) pre-pregnancy (r= 0.52, p< 0.001). Increased uric acid
was more closely related to android fat mass (r= 0.46, p< 0.001) than lean
body mass (r= 0.25, p= 0.01). Pre-pregnancy uric acid was positively
associated with HOMA-IR (r= 0.32, p= 0.001) and CRP (r=0.27, p=
0.007). Uric acid decreased in all women with pregnancy. We found no
association of uric acid pre-pregnancy with BW%, but increased uric acid
in late pregnancy was associated with a decreased BW% (r= -0.31, p=
0.005). There were no differences detected in uric acid pre-pregnancy in
women whose placentas showed evidence of placental underperfusion
compared to those with normal placentas however there was a trend
towards increased uric acid in late pregnancy in women with placental
underperfusion (underperfusion n= 27, mean uric acid= 4.0 ± 0.9 vs. no
underperfusion n=48, 3.6 ± 0.7 mg/dl, p= 0.06). Women who developed
preeclampsia (n=18) had increased uric acid compared to those with
normotensive pregnancy (n=64) both pre-pregnancy and during late
pregnancy (pre-pregnancy = 4.8 ± 1.1 vs. 4.3 ± 0.9 mg/dl, p= 0.04 and
late pregnancy = 4.4 ± 0.8 vs. 3.6 ± 0.7 mg/dl, p< 0.001).
CONCLUSION: Hyperuricemia in the non-pregnant state is associated
with increased BMI and android fat, inflammation, and insulin resistance.
Increased uric acid levels during late pregnancy are associated with
decreased birth weight, with a trend towards an association with placental
underperfusion. We observed increased uric acid levels both prior to
pregnancy and in late pregnancy in women who develop preeclampsia.

S-172
Preeclampsia Risk: Factors beyond the BMI. Suchitra Chandarsekaran*,
Hilary S Gammill*, Darcy R Barry*, Thomas R Easterling*, Ellen A
Schur*. University of Washington, Seattle, WA, United States.
INTRODUCTION: Over the past decade, preeclampsia (PE) rates
have increased by 30%, with maternal obesity as a leading attributable
risk factor. However, 70% of obese women (body mass index, or BMI,
≥30kg/m2) have normal outcomes, suggesting limited predictivity of
BMI alone for PE. In nonpregnant populations, increased visceral fat
mass (VFM) compared to subcutaneous fat mass is a well-established
obesity-associated phenotype that confers a greater risk for metabolic
dysfunction. We hypothesize that VFM and adipokines reflective of VFM
would associate with PE more strongly than BMI alone.
METHODS: We conducted a secondary analysis from a case-control
study of postpartum women with and without prior PE. Subjects were
18 women without prior PE (no PE), 16 women with prior PE with mild
Table of Contents for the Digital Edition of SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018
