Notch expression patterns in the retina: An eye on receptor–ligand distribution during angiogenesis

Hofmann, Jennifer; Iruela‐Arispe, M. Luisa

doi:10.1016/j.modgep.2006.11.002

Cited by 99 publications

(107 citation statements)

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“…Dll4 is usually upregulated by vascular endothelial growth factor in endothelial tip cells, which possess high Dll4 and low Notch (Patel et al, 2005;Hofmann and Luisa Iruela-Arispe, 2007;Benedito et al, 2009). The enhanced Dll4 could activate Notch in the adjacent stalk cells, which exhibit high Notch and low Dll4 (Hofmann and Luisa Iruela-Arispe, 2007;Phng and Gerhardt, 2009). Notch activation sequentially improves the function of microvessels, and lack of Dll4 in stalk cells also permits the proliferation of neighboring tumor cells (Li et al, 2007;Phng and Gerhardt, 2009).…”

Section: Resultsmentioning

confidence: 99%

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Ding

et al. 2011

Oncogene

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Section: Resultsmentioning

confidence: 99%

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Ding

et al. 2011

Oncogene

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“…It is possible that exaggerated S1P 2 signaling in ECs could contribute to patterning defects. We speculate that retinal endothelial tip cell directionality, which is regulated by signaling pathways such as VEGF (23) and Notch (37,43), may be disrupted by aberrant S1P 2 signaling in the context of ROP. As discussed below, such processes may also be influenced by inflammation.…”

Section: Discussionmentioning

confidence: 97%

Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina

Skoura

Sánchez²,

Claffey³

et al. 2007

J. Clin. Invest.

193

153

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Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein-coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of S1P 2 receptor (S1P 2 R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P 2 R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2 -/-mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2 -/-mouse retina. S1P 2 R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P 2 R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P 2 R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization. IntroductionSphingosine 1-phosphate (S1P) is a lipid mediator that regulates various biological processes, such as cell proliferation, migration, survival, and differentiation (1). S1P, generated by the phosphorylation of sphingosine by sphingosine kinase 1 and 2 (Sphk1 and Sphk2), is degraded by S1P-specific phosphatases and a lyase (1). It is also a high-affinity ligand for 5 G protein-coupled S1P receptors, S1P 1 R, S1P 2 R, S1P 3 R, S1P 4 R, and S1P 5 R, which regulate distinct intracellular signaling pathways (2, 3). S1P 1 R, S1P 2 R, and S1P 3 R are widely expressed, whereas S1P 4 and S1P 5 expression is prominent in cells of the immune and nervous systems, respectively. S1P 1 receptor couples exclusively to G i signaling pathway, whereas S1P 2 and S1P 3 receptors couple to G i , G q , and G 12/13 pathways. However, S1P 2 activates G 12/13 potently, whereas S1P 3 activates G q preferentially (4, 5). S1P receptors regulate important physiological functions of the vascular system, such as vascular morphogenesis and maturation, cardiac function, vascular permeability, and tumor angiogenesis (6-10). Indeed, S1p1 receptor-null embryos die due to hemorrhage at E12.5-E14.5. We found that the S1P 1 R signaling in ECs promotes the formation of strong N-cadherin-based junctions between endothelial and vascular smooth muscle cells and thus stabilizes the nascent vasculature (11, 12). However, mice that lack either the S1P 2 R or the S1P 3 R are viable and fertile. Interestingly, S1p1/S1p2-double-null embryos showed a more severe phenotype than S1p1-single-null embryos, suggesting that S1P 2 R also regu-

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“…Delta-like1 is expressed in the venous and arterial vasculature during angiogenesis. 16 Inactivation of Delta-like1 has been observed to impact the overall strength and integrity of the vascular wall. 18 It has been hypothesized that activation of Notch signaling through Delta-like1 might be associated with the abnormal vascular maturation and arteriovenous specification.…”

Section: Notch Signaling In the Rat Avf Modelmentioning

confidence: 99%

Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations

Hu³

et al. 2014

JNS

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R adiosuRgeRy has been used to manage patients with cerebral arteriovenous malformations (AVMs) for more than 4 decades. 56 It offers an important option for patients with AVMs that are unsuitable for resection or embolization. 47,54 Studies reveal that radiosurgery induces thrombosis in AVM vessels, and by 2-3 years approximately 75% of AVM vessels are completely obliterated. 37,48,63 Although overexpression of endothelial adhesion and inflammatory and thrombotic molecules has been reported in irradiated endothelial cells in an AVM model in rats, 22,57,61 Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, Beijing, ChinaObject. Notch signaling has been suggested to promote the development and maintenance of arteriovenous malformations (AVMs), but whether radiosurgery inhibits Notch signaling pathways in AVMs is unknown. The aim of this study was to examine molecular changes of Notch signaling pathways following radiosurgery and to explore mechanisms of radiosurgical obliteration of "nidus" vessels in a rat model of AVMs.Methods. One hundred eleven rats received common carotid artery-to-external jugular vein anastomosis to form an arteriovenous fistula (AVF) model. Six weeks postoperatively, dilated small vessels and capillaries formed a nidus. The rats with AVFs received 25-Gy radiosurgery. The expression of Notch1 and Notch4 receptors and their ligands, Delta-like1 and Delta-like4, Jagged1, Notch downstream gene target HES1, and an apoptotic marker caspase-3 in nidus vessels in the AVF rats was examined immunohistochemically and was quantified using LAS-AF software at 7 time points over a period of 42 days postradiosurgery. The interaction events between Notch1 receptor and Jagged1, as well as Notch4 receptor and Jagged1, were quantified in nidus vessels in the AVF rats using proximity ligation assay at different time points over 42 days postradiosurgery.Results. The expression of Notch1 and Notch4 receptors, Delta-like1, Delta-like4, Jagged1, and HES1 was observed in nidus vessels in the AVF rats pre-and postradiosurgery. Radiosurgery enhanced apoptotic activity (p < 0.05) and inhibited the expression of Notch1 and Notch4 receptors and Jagged1 in the endothelial cells of nidus vessels in the AVF rats at 1, 2, 3, 7, 21, 28, and 42 days postradiosurgery (p < 0.05). Radiosurgery suppressed the interaction events between Notch1 receptor and Jagged1 (p < 0.001) as well as Notch4 receptor and Jagged1 (p < 0.001) in the endothelial cells of nidus vessels in the AVF rats over a period of 42 days postradiosurgery. Radiosurgery induced thrombotic occlusion of nidus vessels in the AVF rats. There was a positive correlation between the percentage of fully obliterated nidus vessels and time after radiosurgery (r = 0.9324, p < 0.001).Conclusions. Radiosurgery inhibits endothelial Notch1 and Notch4 signaling pathways in nidus vessels while inducing thrombotic occlusion of nidus vessels in a rat model of AVMs. The underlying mechanisms of radiosurgeryinduced AVM shrinkage could be a c...

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Notch expression patterns in the retina: An eye on receptor–ligand distribution during angiogenesis

Cited by 99 publications

References 29 publications

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina

Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations

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