Loss of vascular endothelial growth factor a (VEGFA) isoforms in granulosa cells using pDmrt-1-cre or Amhr2-Cre reduces fertility by arresting follicular development and by reducing litter size in female mice

Kevin M. Sargent, Ningxia Lu, Debra T. Clopton, William E. Pohlmeier, Vanessa M. Brauer, Napoleone Ferrara, David W. Silversides, Andrea S. Cupp

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Abstract

Because VEGFA has been implicated in follicle development, the objective of this study was to determine the effects of granulosa- and germ cell-specific VEGFA loss on ovarian morphogenesis, function, and female fertility. pDmrt1-Cre mice were mated to floxed VEGFA mice to develop granulosa-/germ cell-specific knockouts (pDmrt1-Cre;Vegfa-/-). The time from mating to first parturition was increased when pDmrt1-Cre;Vegfa-/- females were mated to control males (P = 0.0008) and tended to be longer for heterozygous females (P < 0.07). Litter size was reduced for pDmrt1-Cre;Vegfa-/- females (P < 0.007). The time between the first and second parturitions was also increased for heterozygous females (P < 0.04) and tended to be increased for pDmrt1-Cre;Vegfa-/- females (P < 0.07). pDmrt1- Cre;Vegfa-/- females had smaller ovaries (P < 0.04), reduced plasma estradiol (P < 0.007), fewer developing follicles (P < 0.008) and tended to have fewer corpora lutea (P < 0.08). Expression of Igf1r was reduced (P < 0.05); expression of Foxo3a tended to be increased (P < 0.06); and both Fshr (P < 0.1) and Sirt6 tended to be reduced (P < 0.06) in pDmrt1- Cre;Vegfa-/- ovaries. To compare VEGFA knockouts, we generated Amhr2-Cre;Vegfa-/- mice that required more time from mating to first parturition (P < 0.003) with variable ovarian size. Both lines had more apoptotic granulosa cells, and vascular staining did not appear different. Taken together these data indicate that the loss of all VEGFA isoforms in granulosa/ germ cells (proangiogenic and antiangiogenic) causes subfertility by arresting follicular development, resulting in reduced ovulation rate and fewer pups per litter.

Original languageEnglish (US)
Article numbere0116332
JournalPloS one
Volume10
Issue number2
DOIs
StatePublished - Feb 6 2015

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Litter Size
vascular endothelial growth factors
Granulosa Cells
follicular development
granulosa cells
litter size
Vascular Endothelial Growth Factor A
Fertility
Protein Isoforms
mice
Cells
germ cells
Germ Cells
parturition
Parturition
Ovary
female fertility
Estradiol
corpus luteum
blood vessels

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Loss of vascular endothelial growth factor a (VEGFA) isoforms in granulosa cells using pDmrt-1-cre or Amhr2-Cre reduces fertility by arresting follicular development and by reducing litter size in female mice. / Sargent, Kevin M.; Lu, Ningxia; Clopton, Debra T.; Pohlmeier, William E.; Brauer, Vanessa M.; Ferrara, Napoleone; Silversides, David W.; Cupp, Andrea S.

In: PloS one, Vol. 10, No. 2, e0116332, 06.02.2015.

Research output: Contribution to journalArticle

Sargent, Kevin M. ; Lu, Ningxia ; Clopton, Debra T. ; Pohlmeier, William E. ; Brauer, Vanessa M. ; Ferrara, Napoleone ; Silversides, David W. ; Cupp, Andrea S. / Loss of vascular endothelial growth factor a (VEGFA) isoforms in granulosa cells using pDmrt-1-cre or Amhr2-Cre reduces fertility by arresting follicular development and by reducing litter size in female mice. In: PloS one. 2015 ; Vol. 10, No. 2.
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abstract = "Because VEGFA has been implicated in follicle development, the objective of this study was to determine the effects of granulosa- and germ cell-specific VEGFA loss on ovarian morphogenesis, function, and female fertility. pDmrt1-Cre mice were mated to floxed VEGFA mice to develop granulosa-/germ cell-specific knockouts (pDmrt1-Cre;Vegfa-/-). The time from mating to first parturition was increased when pDmrt1-Cre;Vegfa-/- females were mated to control males (P = 0.0008) and tended to be longer for heterozygous females (P < 0.07). Litter size was reduced for pDmrt1-Cre;Vegfa-/- females (P < 0.007). The time between the first and second parturitions was also increased for heterozygous females (P < 0.04) and tended to be increased for pDmrt1-Cre;Vegfa-/- females (P < 0.07). pDmrt1- Cre;Vegfa-/- females had smaller ovaries (P < 0.04), reduced plasma estradiol (P < 0.007), fewer developing follicles (P < 0.008) and tended to have fewer corpora lutea (P < 0.08). Expression of Igf1r was reduced (P < 0.05); expression of Foxo3a tended to be increased (P < 0.06); and both Fshr (P < 0.1) and Sirt6 tended to be reduced (P < 0.06) in pDmrt1- Cre;Vegfa-/- ovaries. To compare VEGFA knockouts, we generated Amhr2-Cre;Vegfa-/- mice that required more time from mating to first parturition (P < 0.003) with variable ovarian size. Both lines had more apoptotic granulosa cells, and vascular staining did not appear different. Taken together these data indicate that the loss of all VEGFA isoforms in granulosa/ germ cells (proangiogenic and antiangiogenic) causes subfertility by arresting follicular development, resulting in reduced ovulation rate and fewer pups per litter.",
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AU - Clopton, Debra T.

AU - Pohlmeier, William E.

AU - Brauer, Vanessa M.

AU - Ferrara, Napoleone

AU - Silversides, David W.

AU - Cupp, Andrea S.

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