The switch from quiescence to sprouting of endothelial cells (EC) is the key event in the initiation of angiogenesis. Using an in vitro EC tube-forming assay, we have shown that HESR1, a notch-responsive bHLH transcription factor, is a necessary component of this switch. Mice lacking notch1 or one of its ligands, jagged1, die in utero due to defects in vascular remodeling, demonstrating a critical role for this pathway in vascular development and angiogenesis. Notch acts through HESR1 to maintain EC in a quiescent state, partly through down regulation of VEGFR2. A fall in HESR1 expression is required for the migration and proliferation of EC that is associated with angiogenic sprouting. Vascular development in mice is also critically dependent on wnt signaling, which we have found acts antagonistically to notch in EC by inducing VEGFR2 expression and EC proliferation. These data have led us to the hypothesis that notch and wnt signaling act together to regulate angiogenesis, much as they do in patterning multiple other tissues. The goals of this proposal are to determine: when and where notch and wnt act in this multi-step process; what are the signaling components that are important in these pathways in EC; and what are the downstream targets of these pathways in EC. To achieve these goals we will use a new in vitro angiogenesis assay we have perfected that accurately recapitulates the EC sprouting, migration, alignment, tube formation, branching and anastomosis that are the major stages of angiogenesis in vivo. We will also use HESR1/LacZ knock-in mice to follow the expression of HESR1 in developing vessels in vivo, and monitor the response of this gene to perturbations in notch signaling. Our hope is that these studies will furnish a more thorough understanding of the genes regulating blood vessel patterning during angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060067-06
Application #
6769537
Study Section
Pathology A Study Section (PTHA)
Program Officer
Goldman, Stephen
Project Start
1999-04-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$259,114
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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