# Regulation of Uterine Spiral Artery Remodeling During Primate Pregnancy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $615,555

## Abstract

PROJECT SUMMARY/ABSTRACT: During early human pregnancy, placental extravillous trophoblasts (EVT)
remodel the uterine spiral arteries (UAR) to promote utero-placental blood flow and fetal development.
Impaired UAR underlies pregnancy disorders, e.g. fetal growth restriction and preeclampsia (PE), which result
in maternal and neonatal morbidity/mortality. Conversely, excessive UAR, as in placenta accreta, impairs
vasoregulation after delivery. Despite the importance of UAR to successful pregnancy little is known about
UAR regulation. Using the baboon as a nonhuman primate translational model, we have shown that
advancing the surge in estradiol (E2) from the second to the first trimester suppressed UAR and EVT
expression of vascular endothelial growth factor (VEGF). Therefore, we propose that: (a) the low level of E2 in
the first trimester promotes EVT VEGF expression and UAR and (b) the increase in E2 in the second trimester
suppresses UAR by inhibiting EVT VEGF. Because E2 suppression of UAR was simply associated with a
decrease in EVT VEGF expression, it is not known whether VEGF mediates this process. Therefore, in Aims
1A,B we propose to use contrast enhanced ultrasound (CEU)/microbubble (MB) targeting to deliver the VEGF
gene to the placental basal plate of E2-treated baboons and the sFlt-1 gene which suppresses VEGF
bioavailability to untreated baboons to test the hypotheses that VEGF: (a) mediates the E2-induced
suppression of UAR and (b) promotes UAR during normal pregnancy. A defect in UAR impairs placental
function, leading to an increase in placental sFlt-1 expression/decline in VEGF availability and consequently
disruption of maternal systemic vascular function. Therefore, in Aim 1C, blood flow dynamics will be
determined in baboons to test the hypothesis that the E2-induced increase in sFlt-1/decrease in VEGF
bioavailability results in maternal systemic vascular dysfunction. Because placental dysfunction and vascular
defects in pregnancy disorders occur in a fetal sexual dimorphic manner, in Aim 1D UAR and maternal
vascular function will be determined in pregnancies with male and female fetuses to test the hypothesis that
fetal gender impacts the latter processes. Although E2 typically upregulates VEGF, E2 decreased EVT VEGF
expression. The divergent roles of E2 on VEGF expression may reflect expression/action of estrogen receptor
(ER)α versus ERβ. Therefore, in Aim 1E we will culture baboon EVT to test the hypothesis that ERβ mediates
E2-induced suppression of EVT VEGF expression, migration and invasion. The proposed study is highly
significant as it focuses on the regulation of UAR which when defective underpins abnormal pregnancy. The
experimental paradigm and targeted delivery of VEGF/sFlt-1 genes via CEU/MB are novel cutting-edge
approaches that will establish the role of VEGF on normal and abnormal UAR in a primate with substantial
translational application to humans. Elucidating the role of VEGF on UAR will represent a major sc...

## Key facts

- **NIH application ID:** 10189673
- **Project number:** 5R01HD093070-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Eugene D. Albrecht
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $615,555
- **Award type:** 5
- **Project period:** 2017-09-08 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189673

## Citation

> US National Institutes of Health, RePORTER application 10189673, Regulation of Uterine Spiral Artery Remodeling During Primate Pregnancy (5R01HD093070-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189673. Licensed CC0.

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