Critical role of endothelial Notch1 signaling in postnatal angiogenesis

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State: Public
Version: author
Serval ID
serval:BIB_410CE0DDE5A9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Critical role of endothelial Notch1 signaling in postnatal angiogenesis
Journal
Circulation Research
Author(s)
Takeshita K., Satoh M., Ii M., Silver M., Limbourg F. P., Mukai Y., Rikitake Y., Radtke F., Gridley T., Losordo D. W., Liao J. K.
ISSN
1524-4571 (Electronic)
Publication state
Published
Issued date
01/2007
Peer-reviewed
Oui
Volume
100
Number
1
Pages
70-8
Language
english
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: Jan 5
Abstract
Notch receptors are important mediators of cell fate during embryogenesis, but their role in adult physiology, particularly in postnatal angiogenesis, remains unknown. Of the Notch receptors, only Notch1 and Notch4 are expressed in vascular endothelial cells. Here we show that blood flow recovery and postnatal neovascularization in response to hindlimb ischemia in haploinsufficient global or endothelial-specific Notch1(+/-) mice, but not Notch4(-/-) mice, were impaired compared with wild-type mice. The expression of vascular endothelial growth factor (VEGF) in response to ischemia was comparable between wild-type and Notch mutant mice, suggesting that Notch1 is downstream of VEGF signaling. Treatment of endothelial cells with VEGF increases presenilin proteolytic processing, gamma-secretase activity, Notch1 cleavage, and Hes-1 (hairy enhancer of split homolog-1) expression, all of which were blocked by treating endothelial cells with inhibitors of phosphatidylinositol 3-kinase/protein kinase Akt or infecting endothelial cells with a dominant-negative Akt mutant. Indeed, inhibition of gamma-secretase activity leads to decreased angiogenesis and inhibits VEGF-induced endothelial cell proliferation, migration, and survival. Overexpression of the active Notch1 intercellular domain rescued the inhibitory effects of gamma-secretase inhibitors on VEGF-induced angiogenesis. These findings indicate that the phosphatidylinositol 3-kinase/Akt pathway mediates gamma-secretase and Notch1 activation by VEGF and that Notch1 is critical for VEGF-induced postnatal angiogenesis. These results suggest that Notch1 may be a novel therapeutic target for improving angiogenic response and blood flow recovery in ischemic limbs.
Keywords
Amyloid Precursor Protein Secretases/metabolism Animals *Animals, Newborn Cattle Cell Movement Cell Proliferation Cells, Cultured Endothelial Cells/cytology/drug effects/metabolism Endothelium, Vascular/*metabolism Enzyme Activation Hindlimb/*blood supply Ischemia/metabolism/*physiopathology Male Mice Mice, Knockout *Neovascularization, Physiologic Proto-Oncogene Proteins c-akt/metabolism Receptor, Notch1/chemistry/drug effects/*metabolism Regional Blood Flow Signal Transduction Vascular Endothelial Growth Factor A/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 11:39
Last modification date
20/08/2019 13:40
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