HIF1 activity in granulosa cells is required for FSH-regulated Vegfa expression and follicle survival in mice.
Biol Reprod
; 90(6): 135, 2014 Jun.
Article
em En
| MEDLINE
| ID: mdl-24855100
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator A de Crescimento do Endotélio Vascular
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Translocador Nuclear Receptor Aril Hidrocarboneto
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Hormônio Foliculoestimulante
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Folículo Ovariano
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Células da Granulosa
Limite:
Animals
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Pregnancy
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article