Semaphorin-PlexinD1 Signaling Limits Angiogenic Potential via the VEGF Decoy Receptor sFlt1

Zygmunt, Tomasz; Gay, Carl M.; Blondelle, Jordan; Singh, Manvendra K.; Flaherty, Kathleen; Means, Paula Casey; Herwig, Lukas; Krudewig, Alice; Belting, Heinz‐Georg; Affolter, Markus; Epstein, Jonathan A.; Torres-Vázquez, Jesús

doi:10.1016/j.devcel.2011.06.033

Cited by 149 publications

(141 citation statements)

References 76 publications

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“…More progress has been recently made on the study of how Sema3E prevents angiogenesis in endothelial cells, given the obligatory role of plexin-D1 but not of Nrps in this biological response. Sema3E may counteract the pro-angiogenic effects of VEGF by promoting the expression and release of a soluble VEGF receptor, thus inhibiting VEGF function in developing vessels [55]. In a more direct fashion in endothelial cells, upon stimulation with Sema3E, plexin-D1 initiates a two-pronged mechanism involving R-Ras inactivation and Arf6 activation, thereby affecting the activation status of β1 integrin and its intracellular trafficking, respectively [52] (Figure 2).…”

Section: Sema3ementioning

confidence: 99%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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Angiogenesis, the formation of new blood vessels from preexisting vasculature, is essential for many physiological processes, and aberrant angiogenesis contributes to some of the most prevalent human diseases, including cancer. Angiogenesis is controlled by delicate balance between pro-and anti-angiogenic signals. While pro-angiogenic signaling has been extensively investigated, how developmentally regulated, naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood. In this review, we summarize the current knowledge on how semaphorins and their receptors, plexins and neuropilins, control normal and pathological angiogenesis, with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells. This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies.

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Section: Sema3ementioning

confidence: 99%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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“…These observations suggest that Notch3 function is dispensable for arterialvenous differentiation. Notch signaling also regulates endothelial tip cell selection in the developing vasculature whereby loss of mind bomb or delta-like 4 (dll4) function cause an overabundance of angiogenic cells and ectopic sprouting in ISVs (Leslie et al, 2007;Siekmann and Lawson, 2007;Zygmunt et al, 2011). However, examination of Tg(fli1a:EGFP);notch3 fh332 embryos and larvae between 2 and 3 dpf did not reveal any ectopic angiogenic sprouting ( Fig.…”

Section: Research Articlementioning

confidence: 93%

Notch3 establishes brain vascular integrity by regulating pericyte number

et al. 2014

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Brain pericytes are important regulators of brain vascular integrity, permeability and blood flow. Deficiencies of brain pericytes are associated with neonatal intracranial hemorrhage in human fetuses, as well as stroke and neurodegeneration in adults. Despite the important functions of brain pericytes, the mechanisms underlying their development are not well understood and little is known about how pericyte density is regulated across the brain. The Notch signaling pathway has been implicated in pericyte development, but its exact roles remain ill defined. Here, we report an investigation of the Notch3 receptor using zebrafish as a model system. We show that zebrafish brain pericytes express notch3 and that notch3 mutant zebrafish have a deficit of brain pericytes and impaired blood-brain barrier function. Conditional loss-and gain-of-function experiments provide evidence that Notch3 signaling positively regulates brain pericyte proliferation. These findings establish a new role for Notch signaling in brain vascular development whereby Notch3 signaling promotes expansion of the brain pericyte population.

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“…To test this hypothesis, we performed fate mapping using Tg(fli1a:GAL4FF) ubs4 ;Tg(UAS:kaede) rk8 embryos, which express the photoconvertible protein Kaede in the cytoplasm of all endothelial cells (Hatta et al, 2006;Zygmunt et al, 2011). Endothelial cells within AA1, ICA or CaDI segments were photoconverted from green to red at 24 hpf, and photoconverted cell positions were recorded at 48 hpf (Fig.…”

Section: Resultsmentioning

confidence: 99%

Alk1 controls arterial endothelial cell migration in lumenized vessels

2016

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Heterozygous loss of the arterial-specific TGFβ type I receptor, activin receptor-like kinase 1 (ALK1; ACVRL1), causes hereditary hemorrhagic telangiectasia (HHT). HHT is characterized by development of fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). However, how decreased ALK1 signaling leads to AVMs is unknown. To understand the cellular mis-steps that cause AVMs, we assessed endothelial cell behavior in alk1-deficient zebrafish embryos, which develop cranial AVMs. Our data demonstrate that alk1 loss has no effect on arterial endothelial cell proliferation but alters arterial endothelial cell migration within lumenized vessels. In wild-type embryos, alk1-positive cranial arterial endothelial cells generally migrate towards the heart, against the direction of blood flow, with some cells incorporating into endocardium. In alk1-deficient embryos, migration against flow is dampened and migration in the direction of flow is enhanced. Altered migration results in decreased endothelial cell number in arterial segments proximal to the heart and increased endothelial cell number in arterial segments distal to the heart. We speculate that the consequent increase in distal arterial caliber and hemodynamic load precipitates the flow-dependent development of downstream AVMs.

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Semaphorin-PlexinD1 Signaling Limits Angiogenic Potential via the VEGF Decoy Receptor sFlt1

Cited by 149 publications

References 76 publications

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

Notch3 establishes brain vascular integrity by regulating pericyte number

Alk1 controls arterial endothelial cell migration in lumenized vessels

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