title: 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.
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.
authors: Department of Animal Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors: Kevin M
authors: KM
authors: Sargent
authors: Department of Animal Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors: Ningxia
authors: N
authors: Lu
authors: Department of Animal Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors: Debra T
authors: DT
authors: Clopton
authors: Department of Animal Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors: William E
authors: WE
authors: Pohlmeier
authors: Department of Animal Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors: Vanessa M
authors: VM
authors: Brauer
authors: University of California San Diego School of Medicine, San Diego, CA, United States of America.
authors: Napoleone
authors: N
authors: Ferrara
authors: Department of Veterinary Biomedicine, Faculty of Veterinary Medicine, University of Montreal St-Hyacinthe, Québec, Canada.
authors: David W
authors: DW
authors: Silversides
authors: Department of Animal Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors: Andrea S
authors: AS
authors: Cupp
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004958:Estradiol / Q000097:blood; D005260:Female; D005298:Fertility / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006107:Granulosa Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D008098:Litter Size / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D006080:Ovarian Follicle / Q000254:growth & development*; D020033:Protein Isoforms / Q000172:deficiency; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency*
chemical_list: C110547:DMRT1 protein; D017931:DNA Primers; D020033:Protein Isoforms; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004958:Estradiol