NRP1 acts cell autonomously in endothelium to promote tip cell function during sprouting angiogenesis

Fantin, Alessandro; Vieira, Joaquim Miguel; Plein, Alice; Denti, Laura; Fruttiger, Marcus; Pollard, Jeffrey W.; Ruhrberg, Christiana

doi:10.1182/blood-2012-05-424713

Cited by 147 publications

(161 citation statements)

References 49 publications

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“…Our findings suggest that endothelial cell-derived Sema3A acts in an autocrine fashion on tip cells and reduces filopodial numbers and length during angiogenesis. This concept is supported by studies showing higher Sema3A and Nrp1 expression in tip cells than stalk cells (Strasser et al, 2010;Fantin et al, 2013). Regulation of tip cell morphology was also found in the oxygeninduced retinopathy model, where retinal ganglion cell-derived Sema3A reduced the number of filopodia per tip cell (Joyal et al, 2011).…”

Section: Resultssupporting

confidence: 69%

“…Nrp1 Sema mice express a mutated form of Nrp1, which lacks the Sema-binding domain but maintains its VEGF-induced functions. Sema3A and Nrp1 are more strongly expressed in tip cells than in stalk cells (Strasser et al, 2010;Fantin et al, 2013), suggesting an involvement of Sema3A signaling in sprouting angiogenesis. By taking genetic approaches, we investigated whether Sema3A might act in an autocrine manner to fine-tune the angiogenic process during retinal BV development, which is a well-established model for angiogenesis studies (Geudens and Gerhardt, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

et al. 2016

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Vascular endothelial growth factor (VEGF)-A is a well-known major chemoattractant driver of angiogenesis -the formation of new blood vessels from pre-existing ones. However, the repellent factors that fine-tune this angiogenic process remain poorly characterized. We investigated the expression and functional role of endothelial cellderived semaphorin 3A (Sema3A) in retinal angiogenesis, using genetic mouse models. We found Sema3a mRNA expression in the ganglion cell layer and the presence of Sema3A protein on larger blood vessels and at the growing front of blood vessels in neonatal retinas. The Sema3A receptors neuropilin-1 and plexin-A1 were expressed by retinal blood vessels. To study the endothelial cellspecific role of Sema3A, we generated endothelial cell-specific Sema3A knockout mouse strains by constitutive or inducible vascular endothelial cadherin-Cre-mediated gene disruption. We found that in neonatal retinas of these mice, both the number and the length of tip cell filopodia were significantly increased and the leading edge growth pattern was irregular. Retinal explant experiments showed that recombinant Sema3A significantly decreased VEGF-A-induced filopodia formation. Endothelial cell-specific knockout of Sema3A had no impact on blood vessel density or skin vascular leakage in adult mice. These findings indicate that endothelial cell-derived Sema3A exerts repelling functions on VEGF-A-induced tip cell filopodia and that a lack of this signaling cannot be rescued by paracrine sources of Sema3A.

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Section: Resultssupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

et al. 2016

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“…Such dynamic responses necessitate rapid clearing of activated receptors to finely tune the speed and direction of vessel branching. Signaling through VEGFR2 (and VEGFR3; see below) is enhanced by the coreceptor neuropilin-1 (Nrp1), which promotes tip cell function (7). Although the Nrp1 cytoplasmic domain (and signaling) is dispensable for angiogenesis, it is essential for separation of arteries and veins (8).…”

Section: Tip Cell Selection: Cross-talk Between Vegfr2 and Notchmentioning

confidence: 99%

Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer

Welti¹,

Loges²,

Dimmeler³

et al. 2013

J. Clin. Invest.

542

453

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Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.

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“…3 A and C); therefore, NPCs physically interact with hindbrain vessels. NRP1 is expressed by hindbrain endothelium and NPCs (12), is essential for hindbrain vascularization (20), and cooperates with NRP2 to regulate SEMA3B-mediated NPC division plane orientation in the spinal cord (13). To determine how NRP1 loss affects GZ vascularization and neurogenesis, we compared stagematched Nrp1-null mutant and control hindbrains.…”

Section: Resultsmentioning

confidence: 99%

Regulation of embryonic neurogenesis by germinal zone vasculature

Tata

Wall

Joyce

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In the adult rodent brain, new neurons are born in two germinal regions that are associated with blood vessels, and blood vessels and vessel-derived factors are thought to regulate the activity of adult neural stem cells. Recently, it has been proposed that a vascular niche also regulates prenatal neurogenesis. Here we identify the mouse embryo hindbrain as a powerful model to study embryonic neurogenesis and define the relationship between neural progenitor cell (NPC) behavior and vessel growth. Using this model, we show that a subventricular vascular plexus (SVP) extends through a hindbrain germinal zone populated by NPCs whose peak mitotic activity follows a surge in SVP growth. Hindbrains genetically defective in SVP formation owing to constitutive NRP1 loss showed a premature decline in both NPC activity and hindbrain growth downstream of precocious cell cycle exit, premature neuronal differentiation, and abnormal mitosis patterns. Defective regulation of NPC activity was not observed in mice lacking NRP1 expression by NPCs, but instead in mice lacking NRP1 selectively in endothelial cells, yet was independent of vascular roles in hindbrain oxygenation. Therefore, germinal zone vascularization sustains NPC proliferation in the prenatal brain.blood vessel | neural progenitor | neurogenesis | hindbrain | NRP1

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NRP1 acts cell autonomously in endothelium to promote tip cell function during sprouting angiogenesis

Abstract: Key Points NRP1 promotes brain angiogenesis cell autonomously in endothelium, independently of heterotypic interactions with nonendothelial cells. NRP1 plays a key role in endothelial tip rather than stalk cells during vessel sprouting in the brain.

Cited by 147 publications

References 49 publications

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer

Regulation of embryonic neurogenesis by germinal zone vasculature

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