| The Dll4/Notch pathway controls post-angiogenic blood vessel remodeling and regression by modulating vasoconstriction and blood flow. | |
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MedLine Citation:
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PMID: 21498671 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Post-angiogenic blood vessel pruning/remodeling is crucial to the formation of the definitive vasculature, but little is known about the mechanisms controlling this process. We show that Dll4/Notch pathway regulates vessel regression by modulating vasoconstriction in normal and pathological conditions. Genetic and pharmacological inhibition of the Dll4/Notch pathway prevented retinal capillary regression in the oxygen-induced retinopathy (OIR) model and during normal developmental remodeling. Deletion of the Nrarp, a negative regulator of the Notch pathway, produced an opposite phenotype. Mechanistically, inhibition of Dll4/Notch reduced blood vessel occlusion, maintaining blood flow that is essential for survival of microvessels. Dll4/Notch inhibition upregulated the expression of vasodilators, including adrenomedullin, and suppressed the expression of vasoconstrictors, such as angiotensinogen. Angiotensin II induced rapid non-perfusion and regression of developing retinal capillaries, while the Ace1 inhibitor captopril and AT1 inhibitor losartan attenuated vasoobliteration in the OIR model, as did adrenomedullin, indicating that both pathways are involved in modulating blood vessel perfusion and survival. In contrast, inhibition of VEGF-A did not result in a pervasive loss of retinal capillaries, demonstrating that reduced expression of VEGF-A is not the proximate cause of capillary regression in OIR. Administration of VEGF-A produced changes in blood vessel morphology and gene expression that were distinct from that produced by modulation of Dll4/Notch signaling, indicating that these two pathways can have largely independent functions in vascular remodeling. |
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Authors:
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Ivan B Lobov; Eunice Cheung; Rajeev Wudali; Jingtai Cao; Gabor Halasz; Yi Wei; Aris Economides; Hsin C Lin; Nicholas Papadopoulos; George D Yancopoulos; Stanley J Wiegand |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-15 |
Journal Detail:
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Title: Blood Volume: - ISSN: 1528-0020 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Regeneron Pharmaceuticals, Inc., Tarrytown, NY, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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