Notch Function in Vascular Biology and Angiogenesis

Columbia University Health Sciences, New York NY

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Abstract

ABSTRACT Notch functions to modulate cell-fate decisions during vascular development. The overall objectives are to define roles for Notch during sprouting of blood vessels and remodeling. We explore the hypothesis that angiogenesis is regulated by cross-talk between Notch and integrin signaling pathways;that is we ask if Notch regulation of integrin expression is key to control of endothelial migration, tubulogenesis and sprouting. Our preliminary results show Notch suppresses expression of a2b1 and a6b4 integrins, known angiogenic regulators. In Aim I, we use in vitro assays to explore the consequences of Notch suppression of a2 and a6b4 expression. We propose (1) Notch suppresses a2b1 to affect endothelial migration and/or tube formation in association with collagens/laminins, and (2) Notch suppresses a6/b4 to affect endothelial migration and sprouting in association with laminins. In vitro assays will determine if one can reverse the Notch-suppression of angiogenesis by ectopic expression of a2, b4 and/or a6 integrins. In Aim II, we utilize mice to explore genetic interaction between Notch and integrins, using mice deficient in a2 integrin or defective in b4 signaling, crossed to mice defective for Notch.