Administration of vascular endothelial growth factor Trap during the ‘post-angiogenic’ period of the luteal phase causes rapid functional luteolysis and selective endothelial cell death in the marmoset

Fraser, Hamish M.; Wilson, Helen; Wulff, Christine; Rudge, John S.; Wiegand, Stanley J.

doi:10.1530/rep.1.01064

Cited by 46 publications

(32 citation statements)

References 32 publications

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“…Furthermore, if VEGF is inhibited, the corpus luteum has a rudimentary vascular bed with poor functions (37,39). VEGF is also required for the ongoing function and vasculature maintenance of the mature corpus luteum (3,4,36). These observations are consistent with the those observed in the present study of changes in the mRNA expression levels of VEGF in the luteal development of pregnant rats.…”

Section: Discussionsupporting

confidence: 92%

“…VEGF is fundamental in the physiological angiogenesis and vascularization of the follicular luteinizing granulosa layer during corpus luteum formation (15,16,30,32). Whereas the inhibition of VEGF in vivo during the luteal phase prevents luteal angiogenesis and subsequent progesterone secretion (2)(3)(4)36,37), excess VEGF generation during the vascularization of multiple follicles is also considered to cause ovarian hyperstimulation syndrome (13,38). Furthermore, if VEGF is inhibited, the corpus luteum has a rudimentary vascular bed with poor functions (37,39).…”

Section: Discussionmentioning

confidence: 99%

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Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Zhang

Pan

et al. 2015

Mol Med Report

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Abstract. Vascular endothelial growth factor (VEGF) is vital in normal and abnormal angiogenesis in the ovary, particularly during the early development of the corpus luteum in the ovary. However, the molecular regulation of the expression VEGF during luteal development in vivo remains to be fully elucidated. As the expression of VEGF is mediated by hypoxia-inducible factor (HIF)-1α in luteal cells cultured in vitro, determined in our previous study, the present study was performed to confirm the hypothesis that HIF-1α is induced and then regulates the expression of VEGF and VEGF-dependent luteal development/function in vivo. This was investigated using a pregnant rat model treated with a small-molecule inhibitor of HIF-1α, echinomycin (Ech). The development of the corpus luteum in the pregnant rat ovary was identified via performing assays of the serum progesterone, testosterone and estradiol concentrations by radioimmunoassay, accompanied with determination of the changes in the expression levels of HIF-1α and VEGF by reverse transcription-quantitative polymerase chain reaction at different days of the developmental process. On day 5, serum progesterone levels were markedly increased, whereas serum levels of testosterone and estradiol did not change significantly. On day 17, the highest level of serum progesterone was observed, however, this was not the case for testosterone and estradiol. Further analysis of the expression levels of HIF-1α and VEGF revealed that their changes were consistent with the changes in serum levels of progesterone, which occurred in the development of the corpus luteum in the ovaries of pregnant rats. Further investigation demonstrated that Ech inhibited luteal development through inhibiting the expression of VEGF, mediated by HIF-1α, and subsequent luteal function, which was determined by detecting changes in serum progesterone on days 8 and 14. Taken together, these results demonstrated that HIF-1α-mediated expression of VEGF may be one of the important mechanisms regulating ovarian luteal development in mammals in vivo, which may provide novel strategies in treatment for fertility control and for certain types of ovarian dysfunction, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Zhang

Pan

et al. 2015

Mol Med Report

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“…Administration of VEGF trap, a soluble truncated form of the FLT1 receptor, to marmosets after ovulation causes decreased endothelial cell proliferation, failed development of the microvascular tree, and reduced plasma progesterone (47). Even in the mid-luteal phase, when vascularization is largely complete, VEGFA inhibition elicited a rapid decline in progesterone, increased caspase-3-positive endothelial cells, and decreased endothelial cell density (48). In mice, administration of a truncated sFLT1 receptor inhibited angiogenesis and corpus luteum development and decreased progesterone production, while preexisting vasculature elsewhere in the ovary was unaffected (49).…”

Section: Figurementioning

confidence: 99%

Macrophages regulate corpus luteum development during embryo implantation in mice

et al. 2013

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Macrophages are prominent in the uterus and ovary at conception. Here we utilize the Cd11b-Dtr mouse model of acute macrophage depletion to define the essential role of macrophages in early pregnancy. Macrophage depletion after conception caused embryo implantation arrest associated with diminished plasma progesterone and poor uterine receptivity. Implantation failure was alleviated by administration of bone marrowderived CD11b + F4/80 + monocytes/macrophages. In the ovaries of macrophage-depleted mice, corpora lutea were profoundly abnormal, with elevated Ptgs2, Hif1a, and other inflammation and apoptosis genes and with diminished expression of steroidogenesis genes Star, Cyp11a1, and Hsd3b1. Infertility was rescued by exogenous progesterone, which confirmed that uterine refractoriness was fully attributable to the underlying luteal defect. In normally developing corpora lutea, macrophages were intimately juxtaposed with endothelial cells and expressed the proangiogenic marker TIE2. After macrophage depletion, substantial disruption of the luteal microvascular network occurred and was associated with altered ovarian expression of genes that encode vascular endothelial growth factors. These data indicate a critical role for macrophages in supporting the extensive vascular network required for corpus luteum integrity and production of progesterone essential for establishing pregnancy. Our findings raise the prospect that disruption of macrophage-endothelial cell interactions underpinning corpus luteum development contributes to infertility in women in whom luteal insufficiency is implicated.

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“…Treatment with a VEGF antagonist during the luteal phase, in Macacus and titi monkeys, reduces progesterone secretion (Fraser et al, 2005), the ovarian weight and volume, and increases caspase-3 activity, as compared with untreated individuals (Fraser et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

Guzmán

Macías-Valencia

Fierro

et al. 2015

Animal

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Blood vessel expansion and reduction in the corpus luteum (CL) is regulated by the vascular endothelial growth factor (VEGF) system and linked to the maintenance of the CL. The VEGF system has both angiogenic and antiangiogenic ligands and receptors. Our objective was to evaluate the relationship between the mRNA expression of angiogenic and antiangiogenic members of the VEGF system in the CL, throughout the luteal phase of the oestrous cycle in cows. The CL of 18 cows were collected by transvaginal surgery on days 4, 6, 9, 12, 15 and 18 of the oestrous cycle and the mRNA expression of VEGF system components was evaluated by quantitative real-time PCR. The mRNA expression of VEGF ligands and receptors increased (P < 0.05) from the early-and mid-luteal phase (days 4 to 12) reaching its maximum expression on day 15 of the cycle. We found no expression of VEGF164b throughout the cycle. Expression of sVEGFR1 did not change during the oestrous cycle and exceeded that of the VEGFR1 by 100 times. Nonetheless, as VEGFR1 increased, the relationship between the soluble and membrane receptor decreased (P < 0.01). In contrast, the expression of VEGFR2 was higher than that of its soluble isoform for all days studied, however, the ratio between the membrane-bound and its soluble counterpart decreased continuously throughout the cycle (P < 0.01). Our results show that the expression levels for VEGF ligands, receptors and their antagonistic counterparts are adjusted during CL development and regression, to upregulate angiogenesis early in the oestrous cycle and restrict it at the time of luteolysis.

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Administration of vascular endothelial growth factor Trap during the ‘post-angiogenic’ period of the luteal phase causes rapid functional luteolysis and selective endothelial cell death in the marmoset

Cited by 46 publications

References 32 publications

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Macrophages regulate corpus luteum development during embryo implantation in mice

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

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