Document Detail


Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism.
MedLine Citation:
PMID:  21724832     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Blood vessel networks are typically formed by angiogenesis, a process in which new vessels form by sprouting of endothelial cells from pre-existing vessels. This process is initiated by vascular endothelial growth factor (VEGF)-mediated tip cell selection and subsequent angiogenic sprouting. Surprisingly, we found that VEGF directly controls the expression of Plexin-D1, the receptor for the traditional repulsive axon guidance cue, semaphorin 3E (Sema3E). Sema3E-Plexin-D1 signaling then negatively regulates the activity of the VEGF-induced Delta-like 4 (Dll4)-Notch signaling pathway, which controls the cell fate decision between tip and stalk cells. Using the mouse retina as a model system, we show that Plexin-D1 is selectively expressed in endothelial cells at the front of actively sprouting blood vessels and its expression is tightly controlled by VEGF secreted by surrounding tissues. Therefore, although the Sema3E secreted by retinal neurons is evenly distributed throughout the retina, Sema3E-Plexin-D1 signaling is spatially controlled by VEGF through its regulation of Plexin-D1. Moreover, we show that gain and loss of function of Sema3E and Plexin-D1 disrupts normal Dll4 expression, Notch activity, and tip/stalk cell distribution in the retinal vasculature. Finally, the retinal vasculature of mice lacking sema3E or plexin-D1 has an uneven growing front, a less-branched vascular network, and abnormal distribution of dll4-positive cells. Lowering Notch activity in the mutant mice can reverse this defect, solidifying the observation that Dll4-Notch signaling is regulated by Sema3E-Plexin-D1 and is required for its function in vivo. Together, these data reveal a novel role of Sema3E-Plexin-D1 function in modulating angiogenesis via a VEGF-induced feedback mechanism.
Authors:
Jiha Kim; Won-Jong Oh; Nicholas Gaiano; Yutaka Yoshida; Chenghua Gu
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Genes & development     Volume:  25     ISSN:  1549-5477     ISO Abbreviation:  Genes Dev.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-04     Completed Date:  2011-08-26     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1399-411     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Adhesion Molecules, Neuronal / genetics,  metabolism*
Cell Line
Endothelial Cells / metabolism
Feedback, Physiological / physiology*
Gene Expression Regulation, Developmental*
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mutation
Neovascularization, Physiologic / genetics,  physiology*
Phenotype
Receptors, Notch / metabolism
Retina / cytology,  embryology
Retinal Ganglion Cells / metabolism
Semaphorins / genetics,  metabolism
Signal Transduction*
Vascular Endothelial Growth Factor A / metabolism*
Grant Support
ID/Acronym/Agency:
R01 NS064583/NS/NINDS NIH HHS; R01 NS064583-01A2/NS/NINDS NIH HHS; R01 NS065048/NS/NINDS NIH HHS; R01NS064583/NS/NINDS NIH HHS; R01NS065048/NS/NINDS NIH HHS; T32 NS07484-12/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Cell Adhesion Molecules, Neuronal; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/Receptors, Notch; 0/Semaphorins; 0/Vascular Endothelial Growth Factor A; 0/delta protein; 0/plexin D1, mouse
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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