Intrabursal injection of vascular endothelial growth factor trap in eCG-treated prepubertal rats inhibits proliferation and increases apoptosis of follicular cells involving the PI3K/AKT signaling pathway

Abramovich, Dalhia; Irusta, Griselda; Parborell, Fernanda; Tesone, Marta

doi:10.1016/j.fertnstert.2009.01.127

Cited by 32 publications

(26 citation statements)

References 37 publications

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“…Beyond providing new information regarding regulatory mechanisms of Vegfa gene expression in the ovary, our study also provides insight into the physiological roles of VEGFA in follicle development. Our finding that antral follicle abundance decreased and atresia increased in the Vegfa d/d model relative to WT is fully compatible with older studies that employed intraovarian or intrabursal administration of VEGFA or VEGFA inhibitors [11][12][13]. They are also very similar to a study by Qiu et al [14] that also used a genetic approach to study Vegfa function.…”

Section: Discussionsupporting

confidence: 91%

“…For instance, VEGFA treatment of cultured granulosa cells greatly increases their resistance to apoptosis [8][9][10], and injection of VEGFA into the ovary promotes follicle development and decreases apoptosis [11]. Conversely, the intrabursal administration of a soluble VEGF inhibitor greatly increases granulosa cell apoptosis in antral follicles [12,13], and follicular atresia in normal cycling ovaries is associated with the loss of expression of the VEGFA receptor, VEGFR2 (FLK-1) [8]. Another recent study showed that overexpression of VEGF 165 b (an antiangiogenic isoform of VEGFA) in a transgenic mouse model resulted in reduced female fertility, with ovaries featuring reduced numbers of secondary and tertiary follicles and corpora lutea and increased follicular atresia [14].…”

Section: Introductionmentioning

confidence: 99%

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

Rico

Dodelet-Devillers

Paquet

et al. 2014

Biology of Reproduction

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Rico

Dodelet-Devillers

Paquet

et al. 2014

Biology of Reproduction

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“…However, there remains a lack of knowledge concerning various growth factors and their interactions in the follicle throughout follicle development. A variety of methods have been used in attempts to develop culture systems for GCs in many species, such as the rat (27), porcine (28), sheep (29) and bovine (30). To the best of our knowledge, no report has been published using human ovarian GCs as an in vitro model.…”

Section: Discussionmentioning

confidence: 99%

“…The population consisted of 42 women with normal ovarian function undergoing IVF-ET due to their husbands suffering from azoospermia. The mean age was 27.5±2.8 years (range, [25][26][27][28][29][30][31][32][33][34], and mean BMI was 19.11±1.12 kg/m 2 (range, 16.01-23.58). They had regular menstrual cycle lengths between 25-35 days.…”

Section: Methodsmentioning

confidence: 99%

HOXA10 expression is decreased by testosterone in luteinized granulosa cells in vitro

Tian

Yin

et al. 2012

Mol Med Report

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Abstract. Polycystic ovary syndrome (PCOS) is perhaps the most prevalent endocrine disorder in women of reproductive age, characterized by elevated levels of circulating androgens or clinical manifestations of androgen excess. The specific cytokine profile of PCOS patients is probably related to the lower implantation rate, since follicular fluid appears to function as an embryotrophic agent. For a better understanding of the local regulation of human follicles, the present study investigated the protein expression levels and cellular localization of HOXA10 in granulosa cells (GCs) from women with normal ovarian function undergoing IVF due to their husbands suffering from azoospermia. We demonstrated by immunohistochemical studies that the expression of HOXA10 was mainly localized in the cytoplasm of GCs. Our data indicate that these alterations were associated with changes in the expression of ovarian transcription factors of HOXA10. GC dose-responsive decreases in HOXA10 protein were observed in response to physiological or supraphysiological concentrations (10 -4 to 10 -7 M) of testosterone. These data reveal that testosterone may be involved in HOXA10 gene regulation in GCs. Decreased HOXA10 expression in GCs treated with testosterone suggest that this androgen is responsible for the decreased expression of HOXA10 in PCOS patients.

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“…After boiling for 5 min, extracted proteins from the different CL groups (40 μg protein, C0h, PG4h & PG+S4h) were separated by 10% SDS PAGE and transferred to a nitrocellulose membrane using an electroblotting apparatus as previously described (Peluffo et al, 2007; Abramovich et al, 2009). Non-specific binding sites were blocked overnight (ON) in TBS (4 mM Tris-Cl, pH 7.5, 100 mM NaCl) containing low-fat powdered milk (5%) and Tween 20 (0.5%) at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Local effects of the sphingosine 1‐phosphate on prostaglandin F2alpha‐induced luteolysis in the pregnant rat

Hernandez¹,

Peluffo²,

Bas³

et al. 2009

Molecular Reproduction Devel

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Since the regression of the corpus luteum (CL) occurs via a tightly controlled apoptotic process, studies were designed to determine if local administration of the antiapoptotic agent sphingosine-1-phosphate (S1P) effectively blocks the luteolytic action of PGF-2alpha (PGF-2α). On day 19 of pregnancy, 2 h before systemic PGF-2α administration, rats were injected intrabursa with either S1P or vehicle (control). The activity of four caspases, which contribute to the initial (caspase-2, -8 and -9) and final (caspase-3) events in apoptosis was measured in pooled CL from 4 individual ovaries at 0 h and 4 h after PGF-2α injection. The expression of the phosphorylated form of AKT (pAKT) and TNF-α was analyzed by ELISA. In addition, cell death was evaluated by electronic microscopy (EM) in CL 4 and 36 h after PGF-2α injection. The activity of caspase-2, -3 and -8 was significantly greater by 4h after PGF-2α but not caspase-9 activity. In contrast, expression of pAKT and TNF-α decreased significantly. Administration of S1P suppressed (p<0.05) these effects, decreasing caspase activities and increasing pAKT and TNF-α expression. The administration of S1P also significantly decreased the percentage of luteal apoptotic cells induced by PGF-2α. PGF-2α treatment increased the prevalence of luteal cells with advanced signs of apoptosis (i.e. multiple nuclear fragments, chromatin condensation or apoptotic bodies). S1P treatment suppressed these changes and increased the blood vessel density. These results suggest that S1P blocks the luteolytic effect of the PGF-2α by decreasing caspase-2, -3 and -8 activities and increasing AKT phosphorylation and TNF- α expression.

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Intrabursal injection of vascular endothelial growth factor trap in eCG-treated prepubertal rats inhibits proliferation and increases apoptosis of follicular cells involving the PI3K/AKT signaling pathway

Cited by 32 publications

References 37 publications

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

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

HOXA10 expression is decreased by testosterone in luteinized granulosa cells in vitro

Local effects of the sphingosine 1‐phosphate on prostaglandin F2alpha‐induced luteolysis in the pregnant rat

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