Our long-term goal is to gain a comprehensive understanding of the molecular programs required for the formation of blood vessels. A combination of genetic and cell biological data has established a critical role for Notch signaling in vascular morphogenesis. However, concrete mechanistic insight into Notch's cellular effects in vascular development and differentiation is still far reached. Deletion of Notch 1 results in early embryonic lethality (E.9.5) with multiple defects, including alterations in the heart and vessels. To gain a detailed understanding of Notch1 effects in the vascular compartment, we have generated a mouse model with endothelial-cell specific deletion of Notch1 using a Cre-lox strategy. As in the full deletion, this mouse dies between E9.5-10.5 from collapse of the vascular system, but does not exhibit somitic mesodermal defects and cardiac features seen after global inactivation. Mutant embryos displayed congenital aortic branch defects, reduced aortic lumen, aneurisms, arterial-venous shunts and deregulated vascular branching. We also generated an inducible Cre-lox mouse and subsequently deleted Notch at later developmental time points. Interestingly, ablation of Notch at E10.5 results in hemorrhage and lethality at E13.5. Furthermore, deletion of Notch at E15.5 also leads to multiple hemorrhagic events with lethality at birth. These findings support and expand our understanding of Notch and further highlight the exquisite requirement of this signaling pathway during vascular stabilization and maturation at later time-points. Our current focus is to gain a mechanistic understanding of Notch function at the cellular level and to establish the molecular links of these effects downstream of the Notch signaling pathway. By using a variety of mouse models and in vitro approaches, we propose: (1) to gain a mechanistic understanding of Notch1's effects during vascular development, (2) to explore the contribution of Notch1 in the homeostasis of adult vessels and in pathological conditions, and (3) to evaluate the contribution of Notch-ligand Jagged1 during development. The molecular mapping of vascular morphogenesis is critical to understanding how vessels are formed. Many of the events that take place during development are recapitulated in situations of neoangiogenesis and vascular repair in the adult. Thus, this information is central to the generation of novel and more effective therapies that will enable manipulation of vascular function during pathological conditions. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL085618-01A1
Application #
7257474
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$381,984
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Briot, Anaïs; Jaroszewicz, Artur; Warren, Carmen M et al. (2014) Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells. Dev Cell 31:707-21
Cristofaro, Brunella; Shi, Yu; Faria, Marcella et al. (2013) Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models. Development 140:1720-9
Roodhart, Jeanine M L; He, Huanhuan; Daenen, Laura G M et al. (2013) Notch1 regulates angio-supportive bone marrow-derived cells in mice: relevance to chemoresistance. Blood 122:143-53
Turlo, Kirsten A; Scapa, Jason; Bagher, Pooneh et al. (2013) ?1-integrin is essential for vasoregulation and smooth muscle survival in vivo. Arterioscler Thromb Vasc Biol 33:2325-35
Domigan, Courtney K; Iruela-Arispe, M Luisa (2012) Recent advances in vascular development. Curr Opin Hematol 19:176-83
Turlo, Kirsten A; Noel, Onika D V; Vora, Roshni et al. (2012) An essential requirement for ?1 integrin in the assembly of extracellular matrix proteins within the vascular wall. Dev Biol 365:23-35
Hofmann, Jennifer J; Briot, Anais; Enciso, Josephine et al. (2012) Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome. Development 139:4449-60
Cooley, Marion A; Fresco, Victor M; Dorlon, Margaret E et al. (2012) Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation. Dev Dyn 241:303-14
Iruela-Arispe, M Luisa (2011) LUMENating blood vessels. Dev Cell 20:412-4

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