Vascular Endothelial Growth Factor May Prevent Defective Uterine Artery Remodeling

Vascular endothelial growth factor (VEGF) delivery selectively to the placental basal plate (PBM) may prevent maternal and neonatal impairments caused by defective uterine artery remodeling (UAR), according to a primate study recently accepted for publication in Endocrinology.

Researchers led by Eugene Albrecht, PhD, a professor of medicine in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of Maryland School of Medicine in Baltimore, point out that a defect in remodeling of the uterine spiral arteries early in pregnancy impairs uteroplacental blood flow and fetal development and underpins the etiology of preeclampsia, preterm birth and fetal growth restriction. These adverse conditions of human pregnancy occur in more than 10% of all pregnancies and result in maternal and neonatal morbidity and mortality. “However, despite the absolute importance of UAR to successful pregnancy, the regulation of UAR has not been clearly established,” the authors write.

Albrecht and his team developed a primate model of adverse pregnancy by prematurely elevating estrogen in early baboon pregnancy, which causes a defect in uterine spiral artery remodeling and consequently a reduction in uteroplacental blood flow and fetal development. “Using the baboon as a translational model, we have shown that the low level of ovarian estradiol (E2) during the first trimester of normal pregnancy is essential for promoting UAR,” the authors write. “Thus, simply shifting the normal rise in E2 from the second- to the first-third of pregnancy suppressed UAR and this was associated with a decrease in [extravillous trophoblast] VEGF expression, although this did not prove that VEGF mediated this process.”

For this current study, the researchers noninvasively delivered the VEGF gene specifically to the PBM by contrast-enhanced ultrasonography/microbubble (CEU/MB) technology early in pregnancy in estrogen-treated baboons. “Baboons treated on days 25-59 of gestation (term = 184 days) with E2 alone or with E2 plus VEGF DNA conjugated MB briefly infused via a maternal peripheral vein on days 25, 35, 45 and 55,” the authors write. “At each of these times an ultrasound beam was directed to the PBP to collapse the MB and release VEGF DNA. VEGF DNA labeled MB/contrast agent was localized in the PBP but not the fetus.”

VEGF gene delivery prevented the defect in spiral artery remodeling, showing for the first time that VEGF has a pivotal role in regulating remodeling of these vessels. “Remodeling of uterine arteries >25 μm in diameter on day 60 was 75% lower (P<0.001) in E2-treated (7 ± 2%) than in untreated baboons (30 ± 4%) and restored to normal by E2/VEGF,” the authors write. “VEGF protein levels (signals/nuclear area) within the PBP were 2-fold lower (P<0.01) in E2-treated (4.2 ± 0.9) than in untreated (9.8 ± 2.8) baboons and restored to normal by E2/ VEGF (11.9 ± 1.6), substantiating VEGF transfection.”

The authors go on to write that this study is highly significant from a clinical perspective considering the impact that defective spiral artery transformation has in underpinning the devastating consequences of abnormal human pregnancy and that this study is foundational for future investigation of therapeutic VEGF delivery to prevent the maternal and neonatal impairments caused by defective uterine artery remodeling. “We propose that the low level of ovarian E2 in the first trimester of pregnancy promotes placental EVT VEGF expression and consequently a rapid rate of UAR and the progressive rise in placental E2 levels during the second and third trimesters, as experimentally induced by prematurely elevating E2 in the first trimester, has an important role in repressing EVT VEGF formation and thus the extent of UAR to promote a physiologically normal level of uteroplacental perfusion,” they conclude.

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