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

    loading  Checking for direct PDF access through Ovid


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.

Related Topics

    loading  Loading Related Articles