TY - JOUR
T1 - Vascular endothelial growth factor delivery to placental basal plate promotes uterine artery remodeling in the primate
AU - Babischkin, Jeffery S.
AU - Aberdeen, Graham W.
AU - Lindner, Jonathan R.
AU - Bonagura, Thomas W.
AU - Pepe, Gerald J.
AU - Albrecht, Eugene D.
N1 - Publisher Copyright:
Copyright © 2019 Endocrine Society
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Extravillous trophoblast (EVT) uterine artery remodeling (UAR) promotes placental blood flow, but UAR regulation is unproven. Elevating estradiol (E2) in early baboon pregnancy suppressed UAR and EVT vascular endothelial growth factor (VEGF) expression, but this did not prove that VEGF mediated this process. Therefore, our primate model of prematurely elevating E2 and contrast-enhanced ultrasound cavitation of microbubble (MB) carriers was used to deliver VEGF DNA to the placental basal plate (PBP) to establish the role of VEGF in UAR. Baboons were treated on days 25 to 59 of gestation (term, 184 days) with E2 alone or with E2 plus VEGF DNA-conjugated MBs briefly infused via a maternal peripheral vein on days 25, 35, 45, and 55. At each of these times an ultrasound beam was directed to the PBP to collapse the MBs and release VEGF DNA. VEGF DNA-labeled MBs per contrast agent was localized in the PBP but not the fetus. Remodeling of uterine arteries .25 mm in diameter on day 60 was 75% lower (P, 0.001) in E2-treated (7% 6 2%) than in untreated baboons (30% 6 4%) and was restored to normal by E2/VEGF. VEGF protein levels (signals/nuclear area) within the PBP were twofold lower (P, 0.01) in E2-treated (4.2 6 0.9) than in untreated (9.8 6 2.8) baboons and restored to normal by E2/VEGF (11.9 6 1.6), substantiating VEGF transfection. Thus, VEGF gene delivery selectively to the PBP prevented the decrease in UAR elicited by prematurely elevating E2 levels, establishing the role of VEGF in regulating UAR in vivo during primate pregnancy.
AB - Extravillous trophoblast (EVT) uterine artery remodeling (UAR) promotes placental blood flow, but UAR regulation is unproven. Elevating estradiol (E2) in early baboon pregnancy suppressed UAR and EVT vascular endothelial growth factor (VEGF) expression, but this did not prove that VEGF mediated this process. Therefore, our primate model of prematurely elevating E2 and contrast-enhanced ultrasound cavitation of microbubble (MB) carriers was used to deliver VEGF DNA to the placental basal plate (PBP) to establish the role of VEGF in UAR. Baboons were treated on days 25 to 59 of gestation (term, 184 days) with E2 alone or with E2 plus VEGF DNA-conjugated MBs briefly infused via a maternal peripheral vein on days 25, 35, 45, and 55. At each of these times an ultrasound beam was directed to the PBP to collapse the MBs and release VEGF DNA. VEGF DNA-labeled MBs per contrast agent was localized in the PBP but not the fetus. Remodeling of uterine arteries .25 mm in diameter on day 60 was 75% lower (P, 0.001) in E2-treated (7% 6 2%) than in untreated baboons (30% 6 4%) and was restored to normal by E2/VEGF. VEGF protein levels (signals/nuclear area) within the PBP were twofold lower (P, 0.01) in E2-treated (4.2 6 0.9) than in untreated (9.8 6 2.8) baboons and restored to normal by E2/VEGF (11.9 6 1.6), substantiating VEGF transfection. Thus, VEGF gene delivery selectively to the PBP prevented the decrease in UAR elicited by prematurely elevating E2 levels, establishing the role of VEGF in regulating UAR in vivo during primate pregnancy.
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U2 - 10.1210/en.2019-00059
DO - 10.1210/en.2019-00059
M3 - Article
C2 - 31002314
AN - SCOPUS:85066918577
SN - 0013-7227
VL - 160
SP - 1492
EP - 1505
JO - Endocrinology
JF - Endocrinology
IS - 6
ER -