Neutralization of vascular endothelial growth factor antiangiogenic isoforms is more effective than treatment with proangiogenic isoforms in stimulating vascular development and follicle progression in the perinatal rat ovary

Robin A. Artac, Renee M. McFee, Robyn A. Longfellow Smith, Michelle M. Baltes-Breitwisch, Debra T. Clopton, Andrea S Cupp

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Inhibition of vascular endothelial growth factor A (VEGFA) signal transduction arrests vascular and follicle development. Because antiangiogenic VEGFA isoforms are proposed to block proangiogenic VEGFA isoforms from binding to their receptors, we hypothesized that proangiogenic isoforms promote and antiangiogenic isoforms inhibit these processes. The antiangiogenic isoforms Vegfa-165b and Vegfa-189b were amplified and sequenced from rat ovaries. The Vegfa-165b sequence was 90% homologous to human VEGFA-165B. Quantitative RT-PCR determined that Vegfa-165b mRNA was more abundant around Embryonic Day 18, but Vegfa-189b lacked a distinct pattern of abundance. Antiangiogenic VEGFA isoforms were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the effects of VEGFA isoforms in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with VEGFA-164 or an antibody to antiangiogenic isoforms (anti-VEGFAxxxB). Treatment with 50 ng/ml of VEGFA-164 resulted in a 93% increase in vascular density (P < 0.01), and treated ovaries were composed of fewer primordial follicles (stage 0) and more developing follicles (stages 1-4) than controls (P < 0.04). Ovaries treated with 5 ng/ml of VEGFAxxxB antibody had a 93% increase in vascular density (P < 0.02), with fewer primordial and early primary follicles (stage 1) and more primary, transitional, and secondary follicles (stages 2, 3, and 4, respectively) compared with controls (P < 0.005). We conclude that neutralization of antiangiogenic VEGFA isoforms may be a more effective mechanism of enhancing vascular and follicular development in perinatal rat ovaries than treatment with the proangiogenic isoform VEGFA-164.

Original languageEnglish (US)
Pages (from-to)978-988
Number of pages11
JournalBiology of Reproduction
Volume81
Issue number5
DOIs
StatePublished - Dec 1 2009

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Vascular Endothelial Growth Factor A
Blood Vessels
Ovary
Protein Isoforms
Theca Cells
Antibodies
Granulosa Cells
Signal Transduction
Polymerase Chain Reaction
Messenger RNA

Keywords

  • Follicle
  • Ovary
  • Perinatal rat
  • VEGF
  • Vascular development

ASJC Scopus subject areas

  • Cell Biology

Cite this

Neutralization of vascular endothelial growth factor antiangiogenic isoforms is more effective than treatment with proangiogenic isoforms in stimulating vascular development and follicle progression in the perinatal rat ovary. / Artac, Robin A.; McFee, Renee M.; Longfellow Smith, Robyn A.; Baltes-Breitwisch, Michelle M.; Clopton, Debra T.; Cupp, Andrea S.

In: Biology of Reproduction, Vol. 81, No. 5, 01.12.2009, p. 978-988.

Research output: Contribution to journalArticle

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abstract = "Inhibition of vascular endothelial growth factor A (VEGFA) signal transduction arrests vascular and follicle development. Because antiangiogenic VEGFA isoforms are proposed to block proangiogenic VEGFA isoforms from binding to their receptors, we hypothesized that proangiogenic isoforms promote and antiangiogenic isoforms inhibit these processes. The antiangiogenic isoforms Vegfa-165b and Vegfa-189b were amplified and sequenced from rat ovaries. The Vegfa-165b sequence was 90{\%} homologous to human VEGFA-165B. Quantitative RT-PCR determined that Vegfa-165b mRNA was more abundant around Embryonic Day 18, but Vegfa-189b lacked a distinct pattern of abundance. Antiangiogenic VEGFA isoforms were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the effects of VEGFA isoforms in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with VEGFA-164 or an antibody to antiangiogenic isoforms (anti-VEGFAxxxB). Treatment with 50 ng/ml of VEGFA-164 resulted in a 93{\%} increase in vascular density (P < 0.01), and treated ovaries were composed of fewer primordial follicles (stage 0) and more developing follicles (stages 1-4) than controls (P < 0.04). Ovaries treated with 5 ng/ml of VEGFAxxxB antibody had a 93{\%} increase in vascular density (P < 0.02), with fewer primordial and early primary follicles (stage 1) and more primary, transitional, and secondary follicles (stages 2, 3, and 4, respectively) compared with controls (P < 0.005). We conclude that neutralization of antiangiogenic VEGFA isoforms may be a more effective mechanism of enhancing vascular and follicular development in perinatal rat ovaries than treatment with the proangiogenic isoform VEGFA-164.",
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