HIF1 Activity in Granulosa Cells Is Required for FSH-Regulated Vegfa Expression and Follicle Survival in Mice1

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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 Vegfadelta/delta mice, which lack a hypoxia response element in the Vegfa promoter. Granulosa cells from Vegfadelta/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 Vegfadelta/delta mice had significantly lower Vegfa mRNA levels compared to controls. However, normal Vegfa mRNA levels were detected in the granulosa cells from immature Vegfadelta/delta mice following hCG treatment. Vegfadelta/delta females produced infrequent litters, and their pups died shortly after birth. Ovaries from Vegfadelta/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 Vegfadelta/delta mice relative to controls, and 74% of antral follicles in Vegfadelta/delta ovaries were atretic. Serum progesterone levels in adult Vegfadelta/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.

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