Inhibition of vascular endothelial growth factor receptor signal transduction blocks follicle progression but does not necessarily disrupt vascular development in perinatal rat ovaries

Renee M. McFee, Robin A. Artac, Ryann M. McFee, Debra T. Clopton, Robyn A. Longfellow Smith, Timothy G. Rozell, Andrea S Cupp

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

We hypothesized that vascular endothelial growth factor A (VEGFA) angiogenic isoforms and their receptors, FLT1 and KDR, regulate follicular progression in the perinatal rat ovary. Each VEGFA angiogenic isoform has unique functions (based on its exons) that affect diffusibility, cell migration, branching, and development of large vessels. The Vegfa angiogenic isoforms (Vegfa-120, Vegfa-164, and Vegfa-88) were detected in developing rat ovaries, and quantitative RT-PCR determined that Vegfa-120 and Vegfa-164 mRNA was more abundant after birth, while Vegfa-188 mRNA was highest at Embryonic Day 16. VEGFA and its receptors were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the role of VEGFA in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with 8 μM VEGFR-TKI, a tyrosine kinase inhibitor that blocks FLT1 and KDR. Ovaries treated with VEGFR-TKI had vascular development reduced by 94% (P < 0.0001), with more primordial follicles (stage 0), fewer early primary, transitional, and secondary follicles (stages 1, 3, and 4, respectively), and greater total follicle numbers compared with control ovaries (P < 0.005). V1, an inhibitor specific for KDR, was utilized to determine the effects of only KDR inhibition. Treatment with 30 μM V1 had no effect on vascular density; however, treated ovaries had fewer early primary, transitional, and secondary follicles and more primary follicles (stage 2) compared with control ovaries (P < 0.05). We conclude that VEGFA may be involved in primordial follicle activation and in follicle maturation and survival, which are regulated through vascular-dependent and vascular-independent mechanisms.

Original languageEnglish (US)
Pages (from-to)966-977
Number of pages12
JournalBiology of Reproduction
Volume81
Issue number5
DOIs
StatePublished - Dec 1 2009

Fingerprint

Vascular Endothelial Growth Factor Receptor
Blood Vessels
Ovary
Signal Transduction
Vascular Endothelial Growth Factor A
Protein Isoforms
Theca Cells
Messenger RNA
Granulosa Cells
Protein-Tyrosine Kinases
Cell Movement
Exons
Parturition
Polymerase Chain Reaction

Keywords

  • Follicle
  • Ovary
  • Tyrosine kinase inhibitor
  • VEGF
  • Vascular development

ASJC Scopus subject areas

  • Cell Biology

Cite this

Inhibition of vascular endothelial growth factor receptor signal transduction blocks follicle progression but does not necessarily disrupt vascular development in perinatal rat ovaries. / McFee, Renee M.; Artac, Robin A.; McFee, Ryann M.; Clopton, Debra T.; Longfellow Smith, Robyn A.; Rozell, Timothy G.; Cupp, Andrea S.

In: Biology of Reproduction, Vol. 81, No. 5, 01.12.2009, p. 966-977.

Research output: Contribution to journalArticle

McFee, Renee M. ; Artac, Robin A. ; McFee, Ryann M. ; Clopton, Debra T. ; Longfellow Smith, Robyn A. ; Rozell, Timothy G. ; Cupp, Andrea S. / Inhibition of vascular endothelial growth factor receptor signal transduction blocks follicle progression but does not necessarily disrupt vascular development in perinatal rat ovaries. In: Biology of Reproduction. 2009 ; Vol. 81, No. 5. pp. 966-977.
@article{2f037670d37d432a97b871dc3770e187,
title = "Inhibition of vascular endothelial growth factor receptor signal transduction blocks follicle progression but does not necessarily disrupt vascular development in perinatal rat ovaries",
abstract = "We hypothesized that vascular endothelial growth factor A (VEGFA) angiogenic isoforms and their receptors, FLT1 and KDR, regulate follicular progression in the perinatal rat ovary. Each VEGFA angiogenic isoform has unique functions (based on its exons) that affect diffusibility, cell migration, branching, and development of large vessels. The Vegfa angiogenic isoforms (Vegfa-120, Vegfa-164, and Vegfa-88) were detected in developing rat ovaries, and quantitative RT-PCR determined that Vegfa-120 and Vegfa-164 mRNA was more abundant after birth, while Vegfa-188 mRNA was highest at Embryonic Day 16. VEGFA and its receptors were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the role of VEGFA in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with 8 μM VEGFR-TKI, a tyrosine kinase inhibitor that blocks FLT1 and KDR. Ovaries treated with VEGFR-TKI had vascular development reduced by 94{\%} (P < 0.0001), with more primordial follicles (stage 0), fewer early primary, transitional, and secondary follicles (stages 1, 3, and 4, respectively), and greater total follicle numbers compared with control ovaries (P < 0.005). V1, an inhibitor specific for KDR, was utilized to determine the effects of only KDR inhibition. Treatment with 30 μM V1 had no effect on vascular density; however, treated ovaries had fewer early primary, transitional, and secondary follicles and more primary follicles (stage 2) compared with control ovaries (P < 0.05). We conclude that VEGFA may be involved in primordial follicle activation and in follicle maturation and survival, which are regulated through vascular-dependent and vascular-independent mechanisms.",
keywords = "Follicle, Ovary, Tyrosine kinase inhibitor, VEGF, Vascular development",
author = "McFee, {Renee M.} and Artac, {Robin A.} and McFee, {Ryann M.} and Clopton, {Debra T.} and {Longfellow Smith}, {Robyn A.} and Rozell, {Timothy G.} and Cupp, {Andrea S}",
year = "2009",
month = "12",
day = "1",
doi = "10.1095/biolreprod.109.078071",
language = "English (US)",
volume = "81",
pages = "966--977",
journal = "Biology of Reproduction",
issn = "0006-3363",
publisher = "Society for the Study of Reproduction",
number = "5",

}

TY - JOUR

T1 - Inhibition of vascular endothelial growth factor receptor signal transduction blocks follicle progression but does not necessarily disrupt vascular development in perinatal rat ovaries

AU - McFee, Renee M.

AU - Artac, Robin A.

AU - McFee, Ryann M.

AU - Clopton, Debra T.

AU - Longfellow Smith, Robyn A.

AU - Rozell, Timothy G.

AU - Cupp, Andrea S

PY - 2009/12/1

Y1 - 2009/12/1

N2 - We hypothesized that vascular endothelial growth factor A (VEGFA) angiogenic isoforms and their receptors, FLT1 and KDR, regulate follicular progression in the perinatal rat ovary. Each VEGFA angiogenic isoform has unique functions (based on its exons) that affect diffusibility, cell migration, branching, and development of large vessels. The Vegfa angiogenic isoforms (Vegfa-120, Vegfa-164, and Vegfa-88) were detected in developing rat ovaries, and quantitative RT-PCR determined that Vegfa-120 and Vegfa-164 mRNA was more abundant after birth, while Vegfa-188 mRNA was highest at Embryonic Day 16. VEGFA and its receptors were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the role of VEGFA in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with 8 μM VEGFR-TKI, a tyrosine kinase inhibitor that blocks FLT1 and KDR. Ovaries treated with VEGFR-TKI had vascular development reduced by 94% (P < 0.0001), with more primordial follicles (stage 0), fewer early primary, transitional, and secondary follicles (stages 1, 3, and 4, respectively), and greater total follicle numbers compared with control ovaries (P < 0.005). V1, an inhibitor specific for KDR, was utilized to determine the effects of only KDR inhibition. Treatment with 30 μM V1 had no effect on vascular density; however, treated ovaries had fewer early primary, transitional, and secondary follicles and more primary follicles (stage 2) compared with control ovaries (P < 0.05). We conclude that VEGFA may be involved in primordial follicle activation and in follicle maturation and survival, which are regulated through vascular-dependent and vascular-independent mechanisms.

AB - We hypothesized that vascular endothelial growth factor A (VEGFA) angiogenic isoforms and their receptors, FLT1 and KDR, regulate follicular progression in the perinatal rat ovary. Each VEGFA angiogenic isoform has unique functions (based on its exons) that affect diffusibility, cell migration, branching, and development of large vessels. The Vegfa angiogenic isoforms (Vegfa-120, Vegfa-164, and Vegfa-88) were detected in developing rat ovaries, and quantitative RT-PCR determined that Vegfa-120 and Vegfa-164 mRNA was more abundant after birth, while Vegfa-188 mRNA was highest at Embryonic Day 16. VEGFA and its receptors were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the role of VEGFA in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with 8 μM VEGFR-TKI, a tyrosine kinase inhibitor that blocks FLT1 and KDR. Ovaries treated with VEGFR-TKI had vascular development reduced by 94% (P < 0.0001), with more primordial follicles (stage 0), fewer early primary, transitional, and secondary follicles (stages 1, 3, and 4, respectively), and greater total follicle numbers compared with control ovaries (P < 0.005). V1, an inhibitor specific for KDR, was utilized to determine the effects of only KDR inhibition. Treatment with 30 μM V1 had no effect on vascular density; however, treated ovaries had fewer early primary, transitional, and secondary follicles and more primary follicles (stage 2) compared with control ovaries (P < 0.05). We conclude that VEGFA may be involved in primordial follicle activation and in follicle maturation and survival, which are regulated through vascular-dependent and vascular-independent mechanisms.

KW - Follicle

KW - Ovary

KW - Tyrosine kinase inhibitor

KW - VEGF

KW - Vascular development

UR - http://www.scopus.com/inward/record.url?scp=73349142707&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73349142707&partnerID=8YFLogxK

U2 - 10.1095/biolreprod.109.078071

DO - 10.1095/biolreprod.109.078071

M3 - Article

VL - 81

SP - 966

EP - 977

JO - Biology of Reproduction

JF - Biology of Reproduction

SN - 0006-3363

IS - 5

ER -