Delta-like ligand 4 regulates vascular endothelial growth factor receptor 2–driven luteal angiogenesis through induction of a tip/stalk phenotype in proliferating endothelial cells

García-Pascual, Carmen M.; Zimmermann, Ralf; Ferrero, Hortensia; Shawber, Carrie J.; Kitajewski, Jan; Simón, Carlos; Pellicer, António; Gómez, Raúl

doi:10.1016/j.fertnstert.2013.08.034

Cited by 22 publications

(19 citation statements)

References 25 publications

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“…Notch signaling pathway with the administration of an inhibitor of the g-secretase complex or DLL4 blocking antibody alters follicular development and induces a disruption of the VEGF-dependent luteal angiogenesis (Garcia-Pascual et al 2013, Jovanovic et al 2013. The present data demonstrate a decrease in progesterone production when CLs obtained from pregnant or superovulated rats were incubated with DAPT, a g-secretase inhibitor.…”

Section: Link Between Notch and Progesterone In CL Functionsupporting

confidence: 49%

“…In addition, to demonstrate in our experimental model that the action of DAPT is specifically related with the inhibition of the Notch pathway, we blocked Notch action with an antibody against DLL4, the Notch ligand with a well-described luteotropic role (Hernandez et al 2011, Fraser et al 2012, Garcia-Pascual et al 2013. This experiment showed a decrease in luteal progesterone production, confirming that the Notch system is involved in luteal function.…”

Section: Link Between Notch and Progesterone In CL Functionmentioning

confidence: 68%

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A link between Notch and progesterone maintains the functionality of the rat corpus luteum

et al. 2015

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In this study, we investigated the interaction between the Notch pathway and progesterone to maintain the functionality of the corpus luteum (CL). When Notch signaling is activated, the g-secretase complex releases the active intracellular domains (NICD) of their receptors, which exert survival effects. We designed studies to analyze whether the in vitro inhibition of Notch affects progesterone production, steroidogenic regulators, apoptotic parameters, and signaling transduction pathways in the cultures of CL isolated from pregnant and superovulated rats. We detected a decrease in progesterone production when corpora lutea (CL) were incubated with N-(N-(3,5-difluorophenacetyl-L-alanyl))-S-phenylglycine t-butyl ester (DAPT), a g-secretase inhibitor. This effect could be in part due to the decrease detected in the CL protein levels of P450scc because STAR and 3b-hydroxysteroid dehydrogenase were not affected by Notch inhibition. Besides, the addition of aminoglutethimide to the CL culture medium decreased NICD of NOTCH1. We observed an increase in the expression of active CASPASE3 (CASP3) after inhibition by Notch, which was reversed by the presence of progesterone. The BAX:BCLX L ratio was increased in CL treated with DAPT and the presence of progesterone reversed this effect. In addition, phosphorylation of AKT was inhibited in CL treated with DAPT, but had no effect on ERK activation. To demonstrate that the action of DAPT is specifically related with the inhibition of Notch, CLs were incubated with DLL4 antibody and a decrease in progesterone production was detected. These results suggest the existence of a novel link between progesterone and the Notch signaling pathway to maintain the functionality of the CL.

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Section: Link Between Notch and Progesterone In CL Functionsupporting

confidence: 49%

Section: Link Between Notch and Progesterone In CL Functionmentioning

confidence: 68%

A link between Notch and progesterone maintains the functionality of the rat corpus luteum

et al. 2015

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“…Several Notch components are expressed within the ovarian vasculature including Dll4 located at the tip of endothelial cells within the thecal layer (Jovanovic et al 2013) and growing luteal vessels (Garcia-Pascual et al 2013); Notch3 within endothelial cells and vascular smooth muscle cells (Jovanovic et al 2013); and Notch1 , Notch4, and Jag1 within thecal layer endothelial and vascular smooth muscle cells (Vorontchikhina et al 2005, Jovanovic et al 2013). …”

Section: Notch Pathway In the Ovarian Vasculaturementioning

confidence: 99%

“…In immature female mice treated with PMSG and hCG, to stimulate follicle development, injection of an inhibitory DLL4 antibody promotes promiscuous expression of Dll4 leading to increased, but non-functional, vascularization that is associated with decreased progesterone production (Figure 3D) (Garcia-Pascual et al 2013). In contrast, suppression of Notch signaling using a pan-Notch inhibitor, compound E ((s,s)-2-(3,5-Difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide), causes a reduction in ovarian weight and estrogen production as a result of uninhibited, but highly disorganized, vascular proliferation that culminates in blocked follicle development at the preovulatory stage (Jovanovic et al 2013).…”

Section: Notch Pathway In the Ovarian Vasculaturementioning

confidence: 99%

The role of Notch signaling in the mammalian ovary

Vanorny

Mayo

2017

Reproduction

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The Notch pathway is a contact-dependent, or juxtacrine, signaling system that is conserved in metazoan organisms and is important in many developmental processes. Recent investigations have demonstrated that the Notch pathway is active in both the embryonic and postnatal ovary and plays important roles in events including follicle assembly and growth, meiotic maturation, ovarian vasculogenesis, and steroid hormone production. Ovarian pathologies resulting from disruption of the Notch pathway in mice affect meiotic spindle assembly, follicle histogenesis, granulosa cell proliferation and survival, corpora luteal function, and ovarian neovascularization. These aberrations result in abnormal folliculogenesis and reduced fertility. Knowledge of the cellular interactions facilitated by the Notch pathway is an important area for continuing research and future studies are expected to enhance our understanding of ovarian function and provide critical insights for improving reproductive health. This review focuses on the expression of Notch pathway components in the ovary, and on the multiple functions of Notch signaling in follicle assembly, maturation, and development. We focus on the mouse, where genetic investigations are possible, and relate this information to the human ovary.

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“…In the absence of Notch signaling, ECs continue to form sprouts in response to VEGF, resulting in more sprouts and branches per sprout, as has been documented in different model systems such as zebrafish embryos [32], mouse retina [3335] and xenograft tumors [3638]. More recently, a role of Notch signaling has also been demonstrated in decidual angiogenesis and luteal angiogenesis [39]. Jagged1, another type of Notch ligands, plays a proangiogenic role in mice by antagonizng Dll4-Notch signaling in cells expressing Fringe family glycosyltransferases (Figure 1) [34].…”

Section: Sprouting Angiogenesismentioning

confidence: 85%

Notch signaling in blood vessels: from morphogenesis to homeostasis

Zhang

Yan

Chen

et al. 2014

Sci. China Life Sci.

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Notch signaling is an evolutionarily conserved intercellular signaling pathway that plays numerous crucial roles in vascular development and physiology. Compelling evidence indicates that Notch signaling is vital for vascular morphogenesis including arterial and venous differentiation and endothelial tip and stalk cell specification during sprouting angiogenesis and also vessel maturation featured by mural cell differentiation and recruitment. Notch signaling is also required for vascular homeostasis in adults by keeping quiescent phalanx cells from re-entering cell cycle and by modulating the behavior of endothelial progenitor cells. We will summarize recent advances of Notch pathway in vascular biology with special emphasis on the underlying molecular mechanisms.

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Delta-like ligand 4 regulates vascular endothelial growth factor receptor 2–driven luteal angiogenesis through induction of a tip/stalk phenotype in proliferating endothelial cells

Cited by 22 publications

References 25 publications

A link between Notch and progesterone maintains the functionality of the rat corpus luteum

A link between Notch and progesterone maintains the functionality of the rat corpus luteum

The role of Notch signaling in the mammalian ovary

Notch signaling in blood vessels: from morphogenesis to homeostasis

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