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VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Sun Yat Sen University, Peoples R China.
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2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 44, E5944-E5953 p.Article in journal (Refereed) Published
Abstract [en]

Physiological functions of vascular endothelial growth factor (VEGF)-B remain an enigma, and deletion of the Vegfb gene in mice lacks an overt phenotype. Here we show that knockdown of Vegfba, but not Vegfbb, in zebrafish embryos by specific morpholinos produced a lethal phenotype owing to vascular and neuronal defects in the brain. Vegfba morpholinos also markedly prevented development of hyaloid vasculatures in the retina, but had little effects on peripheral vascular development. Consistent with phenotypic defects, Vegfba, but not Vegfaa, mRNA was primarily expressed in the brain of developing zebrafish embryos. Interestingly, in situ detection of Neuropilin1 (Nrp1) mRNA showed an overlapping expression pattern with Vegfba, and knockdown of Nrp1 produced a nearly identically lethal phenotype as Vegfba knockdown. Furthermore, zebrafish VEGF-Ba protein directly bound to NRP1. Importantly, gain-of-function by exogenous delivery of mRNAs coding for NRP1-binding ligands VEGF-B or VEGF-A to the zebrafish embryos rescued the lethal phenotype by normalizing vascular development. Similarly, exposure of zebrafish embryos to hypoxia also rescued the Vegfba morpholino-induced vascular defects in the brain by increasing VEGF-A expression. Independent evidence of VEGF-A gain-of-function was provided by using a functionally defective Vhl-mutant zebrafish strain, which again rescued the Vegfba morpholino-induced vascular defects. These findings show that VEGF-B is spatiotemporally required for vascular development in zebrafish embryos and that NRP1, but not VEGFR1, mediates the essential signaling.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2015. Vol. 112, no 44, E5944-E5953 p.
Keyword [en]
VEGF-B; Neuropilin; zebrafish; vasculature; brain development
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-123063DOI: 10.1073/pnas.1510245112ISI: 000364164900009PubMedID: 26483474OAI: oai:DiVA.org:liu-123063DiVA: diva2:876599
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute Distinguished Professor Award; Torsten Soderbergs Foundation; European Research Council advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation advanced grant; Alice Wallenberg Foundation

Available from: 2015-12-04 Created: 2015-12-03 Last updated: 2016-04-25

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Jensen, LasseCao, Yihai
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Division of Cardiovascular MedicineFaculty of Medicine and Health Sciences
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