Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch

Aspalter, Irene M.; Gordon, Emma; Dubrac, Alexandre; Ragab, Anan; Narloch, Jarek; Vizán, Pedro; Geudens, Ilse; Collins, Russell T.; Franco, Cláudio A.; Abrahams, Cristina; Thurston, Gavin; Fruttiger, Marcus; Rosewell, Ian; Eichmann, Anne; Gerhardt, Holger

doi:10.1038/ncomms8264

Cited by 146 publications

(169 citation statements)

References 67 publications

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“…Conversely, endothelialresident NRP-1 is critical for proper CNS vascularization as deletion of endothelial NRP-1 reduces vessel branching in the hindbrain 12,30 and limits tip formation and branching in the retina. 31 Taken with previous work identifying the key contribution of NRP-1 þ myeloid cells to pathologic retinal angiogenesis, 23 data presented in this study drew a dichotomous role for NRP-1 in myeloid cells where it is dispensable for adequate retinal developmental vascularization yet obligate for pathologic retinal angiogenesis.…”

Section: Discussionsupporting

confidence: 70%

Neuropilin-1–Expressing Microglia Are Associated With Nascent Retinal Vasculature Yet Dispensable for Developmental Angiogenesis

Dejda

Mawambo

Daudelin

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Dejda A, Mawambo G, Daudelin JF, et al. Neuropilin-1-expressing microglia are associated with nascent retinal vasculature yet dispensable for developmental angiogenesis. Invest Ophthalmol Vis Sci. 2016;57:153057: -153657: . DOI:10.1167 PURPOSE. Neuropilin-1 (NRP-1) is a transmembrane receptor that is critical for vascular development within the central nervous system (CNS). It binds and influences signaling of several key angiogenic factors, such as VEGF-165, semaphorin 3A, platelet derived growth factor, and more. Neuropilin-1 is expressed by neurons and endothelial cells as well as a subpopulation of proangiogenic macrophages/microglia that are thought to interact with endothelial tip cells to promote vascular anastomosis during brain vascularization. We previously demonstrated a significant role for NRP-1 in macrophage chemotaxis and showed that NRP-1-expressing microglia are major contributors to pathologic retinal angiogenesis. Given this influence on CNS angiogenesis, we now investigated the involvement of microgliaresident NRP-1 in developmental retinal vascularization. METHODS.We followed NRP-1 expressing microglia during retinal development. We used LysM-cre myeloid lineage-driver cre mice to reduce expression of NRP-1 in retinal myeloidderived cells and performed a comprehensive morphometric analysis of retinal vasculature during development. RESULTS.We provide evidence that NRP-1 þ microglia are present throughout the retina during vascular development with a preference for the non-vascularized retina. Using LysM-Cre/ Nrp1 fl/fl mice, we reduced NRP-1 expression by~65% in retinal microglia and demonstrate that deficiency in NRP-1 in these microglia does not impair retinal angiogenesis.CONCLUSIONS. Our data draw a dichotomous role for NRP-1 in cells of myeloid lineage where it is dispensable for adequate retinal developmental vascularization yet obligate for pathologic retinal angiogenesis.

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Section: Discussionsupporting

confidence: 70%

Neuropilin-1–Expressing Microglia Are Associated With Nascent Retinal Vasculature Yet Dispensable for Developmental Angiogenesis

Dejda

Mawambo

Daudelin

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Importantly, our recent study has demonstrated that neuropilin-1 (NRP1), which is highly expressed in tip cells, represses ALK5-and ALK1-dependent SMAD activation. This repression is relieved in stalk cells, where activation of Notch decreases expression of Nrp1 (Aspalter et al, 2015). The results of this study challenged the concept of the tip cell being the default state of endothelial cells.…”

Section: Introductionmentioning

confidence: 49%

cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner

et al. 2016

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cAMP-dependent protein kinase A (PKA) is a ubiquitously expressed serine/threonine kinase that regulates a variety of cellular functions. Here, we demonstrate that endothelial PKA activity is essential for vascular development, specifically regulating the transition from sprouting to stabilization of nascent vessels. Inhibition of endothelial PKA by endothelial cell-specific expression of dominant-negative PKA in mice led to perturbed vascular development, hemorrhage and embryonic lethality at mid-gestation. During perinatal retinal angiogenesis, inhibition of PKA resulted in hypersprouting as a result of increased numbers of tip cells. In zebrafish, cell autonomous PKA inhibition also increased and sustained endothelial cell motility, driving cells to become tip cells. Although these effects of PKA inhibition were highly reminiscent of Notch inhibition effects, our data demonstrate that PKA and Notch independently regulate tip and stalk cell formation and behavior.

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“…Moya et al, for example, have found that Smad1/5‐mediated bone morphogenetic protein signaling could cooperate with Notch signaling in the selection of tip and stalk cells during angiogenic sprouting 50. A recent study also indicated that neuropilin 1, a coreceptor of VEGFR, suppresses the stalk cell phenotype by limiting Smad2/3 activation through ALK1 and ALK5 and that Notch signaling downregulates neuropilin 1, leading to relief of ALK1 and ALK5 inhibition to drive stalk cell behavior 51. In this study, we found that miR‐342‐5p could be a central, although not strong, coordinator of Notch, VEGFR, and TGF‐β signaling pathways to ultimately result in repression of VEGFR signaling (Figure 8D).…”

Section: Discussionmentioning

confidence: 99%

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Yan

Cao

Liang

et al. 2016

JAHA

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BackgroundEndothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.Methods and ResultsSmall RNA sequencing initially identified miR‐342‐5p as a novel downstream molecule of Notch signaling in ECs. Reporter assay, quantitative reverse transcription polymerase chain reaction and Western blot analysis indicated that miR‐342‐5p targeted endoglin and modulated transforming growth factor β signaling by repressing SMAD1/5 phosphorylation in ECs. Transfection of miR‐342‐5p inhibited EC proliferation and lumen formation and reduced angiogenesis in vitro and in vivo, as assayed by using a fibrin beads–based sprouting assay, mouse aortic ring culture, and intravitreal injection of miR‐342‐5p agomir in P3 pups. Moreover, miR‐342‐5p promoted the migration of ECs, accompanied by reduced endothelial markers and increased mesenchymal markers, indicative of increased endothelial–mesenchymal transition. Transfection of endoglin at least partially reversed endothelial–mesenchymal transition induced by miR‐342‐5p. The expression of miR‐342‐5p was upregulated by transforming growth factor β, and inhibition of miR‐342‐5p attenuated the inhibitory effects of transforming growth factor β on lumen formation and sprouting by ECs. In addition, VEGF repressed miR‐342‐5p expression, and transfection of miR‐342‐5p repressed VEGFR2 and VEGFR3 expression and VEGF‐triggered Akt phosphorylation in ECs. miR‐342‐5p repressed angiogenesis in a laser‐induced choroidal neovascularization model in mice, highlighting its clinical potential.ConclusionsmiR‐342‐5p acts as a multifunctional angiogenic repressor mediating the effects and interaction among angiogenic pathways.

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Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch

Cited by 146 publications

References 67 publications

Neuropilin-1–Expressing Microglia Are Associated With Nascent Retinal Vasculature Yet Dispensable for Developmental Angiogenesis

Neuropilin-1–Expressing Microglia Are Associated With Nascent Retinal Vasculature Yet Dispensable for Developmental Angiogenesis

cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

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