Vascular endothelial growth factor delivery to placental basal plate promotes uterine artery remodeling in the primate

Jeffery S. Babischkin, Graham W. Aberdeen, Jonathan Lindner, Thomas W. Bonagura, Gerald J. Pepe, Eugene D. Albrecht

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)1492-1505
    Number of pages14
    JournalEndocrinology
    Volume160
    Issue number6
    DOIs
    StatePublished - Jun 1 2019

    Fingerprint

    Uterine Artery
    Primates
    Vascular Endothelial Growth Factor A
    Papio
    DNA
    Trophoblasts
    Pregnancy
    Microbubbles
    Contrast Media
    Transfection
    Estradiol
    Veins

    ASJC Scopus subject areas

    • Endocrinology

    Cite this

    Vascular endothelial growth factor delivery to placental basal plate promotes uterine artery remodeling in the primate. / Babischkin, Jeffery S.; Aberdeen, Graham W.; Lindner, Jonathan; Bonagura, Thomas W.; Pepe, Gerald J.; Albrecht, Eugene D.

    In: Endocrinology, Vol. 160, No. 6, 01.06.2019, p. 1492-1505.

    Research output: Contribution to journalArticle

    Babischkin, Jeffery S. ; Aberdeen, Graham W. ; Lindner, Jonathan ; Bonagura, Thomas W. ; Pepe, Gerald J. ; Albrecht, Eugene D. / Vascular endothelial growth factor delivery to placental basal plate promotes uterine artery remodeling in the primate. In: Endocrinology. 2019 ; Vol. 160, No. 6. pp. 1492-1505.
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    abstract = "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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