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. ? ? ?
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