title: HIF1 activity in granulosa cells is required for FSH-regulated Vegfa expression and follicle survival in mice.
abstract: Recent evidence has suggested that vascular endothelial growth factor A (VEGFA) is an important regulator of ovarian follicle development and survival. Both LH and FSH regulate Vegfa expression in granulosa cells and signal via the transcription factor hypoxia inducible factor 1 (HIF1). To further study the mechanism of action of HIF1 in the regulation of Vegfa, we studied Vegfa(delta/delta) mice, which lack a hypoxia response element in the Vegfa promoter. Granulosa cells from Vegfa(delta/delta) mice failed to respond to FSH or LH with an increase in Vegfa mRNA expression in vitro, and granulosa cells isolated from eCG-treated immature Vegfa(delta/delta) mice had significantly lower Vegfa mRNA levels compared to controls. However, normal Vegfa mRNA levels were detected in the granulosa cells from immature Vegfa(delta/delta) mice following hCG treatment. Vegfa(delta/delta) females produced infrequent litters, and their pups died shortly after birth. Ovaries from Vegfa(delta/delta) mice were much smaller than controls and contained few antral follicles and corpora lutea. Antral follicles numbers were decreased by nearly 50% in ovaries from Vegfa(delta/delta) mice relative to controls, and 74% of antral follicles in Vegfa(delta/delta) ovaries were atretic. Serum progesterone levels in adult Vegfa(delta/delta) females were significantly lower, apparently reflecting reduced numbers of corpora lutea. This study demonstrates for the first time the requirement of HIF1 for FSH-regulated Vegfa expression in vivo and that HIF1 acts via a single hypoxia response element in the Vegfa promoter to exert its regulatory functions. Our findings also further define the physiological role of VEGFA in follicle development.
authors.affiliation: Centre de Recherche en Reproduction Animale, Université de Montréal, St-Hyacinthe, Québec, Canada.
authors.forename: Charlène
authors.initials: C
authors.lastname: Rico
authors.affiliation: Centre de Recherche en Reproduction Animale, Université de Montréal, St-Hyacinthe, Québec, Canada.
authors.forename: Aurore
authors.initials: A
authors.lastname: Dodelet-Devillers
authors.affiliation: Centre de Recherche en Reproduction Animale, Université de Montréal, St-Hyacinthe, Québec, Canada.
authors.forename: Marilène
authors.initials: M
authors.lastname: Paquet
authors.affiliation: Centre de Recherche en Reproduction Animale, Université de Montréal, St-Hyacinthe, Québec, Canada.
authors.forename: Mayra
authors.initials: M
authors.lastname: Tsoi
authors.affiliation: Centre de Recherche en Reproduction Animale, Université de Montréal, St-Hyacinthe, Québec, Canada.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lapointe
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Centre de Recherche en Reproduction Animale, Université de Montréal, St-Hyacinthe, Québec, Canada derek.boerboom@umontreal.ca.
authors.forename: Derek
authors.initials: D
authors.lastname: Boerboom
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003338:Corpus Luteum / Q000502:physiology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006062:Gonadotropins / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size / Q000502:physiology; D006080:Ovarian Follicle / Q000166:cytology / Q000502:physiology*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012098:Reproduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C497397:Arnt protein, mouse; D006062:Gonadotropins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D005640:Follicle Stimulating Hormone
keywords: HIF1; VEGFA; follicular development; granulosa cells