title: Developmental Programming: Does Prenatal Steroid Excess Disrupt the Ovarian VEGF System in Sheep?
abstract: Prenatal testosterone (T), but not dihydrotestosterone (DHT), excess disrupts ovarian cyclicity and increases follicular recruitment and persistence. We hypothesized that the disruption in the vascular endothelial growth factor (VEGF) system contributes to the enhancement of follicular recruitment and persistence in prenatal T-treated sheep. The impact of T/DHT treatments from Days 30 to 90 of gestation on VEGFA, VEGFB, and their receptor (VEGFR-1 [FLT1], VEGFR-2 [KDR], and VEGFR-3 [FLT4]) protein expression was examined by immunohistochemistry on Fetal Days 90 and 140, 22 wk, 10 mo (postpubertal), and 21 mo (adult) of age. Arterial morphometry was performed in Fetal Day 140 and postpubertal ovaries. VEGFA and VEGFB expression were found in granulosa cells at all stages of follicular development with increased expression in antral follicles. VEGFA was present in theca interna, while VEGFB was present in theca interna/externa and stromal cells. All three receptors were expressed in the granulosa, theca, and stromal cells during all stages of follicular development. VEGFR-3 increased with follicular differentiation with the highest level seen in the granulosa cells of antral follicles. None of the members of the VEGF family or their receptor expression were altered by age or prenatal T/DHT treatments. At Fetal Day 140, area, wall thickness, and wall area of arteries from the ovarian hilum were larger in prenatal T- and DHT-treated females, suggestive of early androgenic programming of arterial differentiation. This may facilitate increased delivery of endocrine factors and thus indirectly contribute to the development of the multifollicular phenotype.
authors.affiliation: Department of Morphological Sciences, Faculty of Veterinary Sciences, National University of Litoral, Esperanza, Santa Fe, Argentina Argentine National Research Council (CONICET), Esperanza, Santa Fe, Argentina.
authors.forename: Hugo Héctor
authors.initials: HH
authors.lastname: Ortega
authors.affiliation: Department of Pediatrics and the Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Almudena
authors.initials: A
authors.lastname: Veiga-Lopez
authors.affiliation: Department of Pediatrics and the Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Sreedharan
authors.affiliation: Department of Morphological Sciences, Faculty of Veterinary Sciences, National University of Litoral, Esperanza, Santa Fe, Argentina Argentine National Research Council (CONICET), Esperanza, Santa Fe, Argentina.
authors.forename: Melisa María
authors.initials: MM
authors.lastname: del Luján Velázquez
authors.affiliation: Department of Morphological Sciences, Faculty of Veterinary Sciences, National University of Litoral, Esperanza, Santa Fe, Argentina Argentine National Research Council (CONICET), Esperanza, Santa Fe, Argentina.
authors.forename: Natalia Raquel
authors.initials: NR
authors.lastname: Salvetti
authors.affiliation: Department of Pediatrics and the Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan vasantha@umich.edu.
authors.forename: Vasantha
authors.initials: V
authors.lastname: Padmanabhan
mesh_terms: D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D007150:Immunohistochemistry; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010053:Ovary / Q000098:blood supply / Q000254:growth & development / Q000378:metabolism*; D011247:Pregnancy; D012039:Regional Blood Flow / Q000187:drug effects; D034561:Sheep, Domestic; D013256:Steroids / Q000494:pharmacology*; D013739:Testosterone / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D013256:Steroids; D042461:Vascular Endothelial Growth Factor A; D013196:Dihydrotestosterone; D013739:Testosterone; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: PCOS; VEGF; ovary; sheep; testosterone