Vascular development entails multiple cell fate decisions that specify a diverse array of vascular structures, which include veins, arteries, capillaries, lymphatics, and specialized vascular beds of organs. Genetic studies have revealed that Notch plays a central role in the specification of arterial versus venous vasculature. Notch function is critical for remodelling and patterning of the vasculature, suggesting an additional role for Notch in regulating angiogenesis, a multistep process that requires endothelial cells (ECs) to respond to a variety of angiogenic stimuli. Notch proteins are receptors that modulate the ability of cells to respond to external cues, thus making them ideal regulators of angiogenesis. This chapter reviews in vivo and in vitro studies that have provided insights into Notch functions in the endothelium during development and in postnatal life. These studies show that Notch not only mediates specialization of the endothelium, but also has both positive and negative influences on the process of angiogenesis.

NOTCH AND NOTCH LIGAND GENES

The study of Notch started in 1917, when the famed geneticist, Thomas Hunt Morgan, first described a strain of Drosophila with “notched” wings. Notch genes were first molecularly identified during the 1980s, through genetic analysis of invertebrate organisms Caenorhabditis elegans (1) and Drosophila (2). Mutations in the Notch genes were described as affecting “cell fate determination,” a process by which cells use molecular signals to specify distinct cellular fates. During the 1990s, the identification of Notch genes expressed in the vasculature (3,4) and both the functional analysis of Notch ligand Jagged in mice (5) and Notch gene target gridlock in zebrafish (6,7) began an era of vascular study of Notch.