The γ-secretase complex is a high-molecular-weight complex that consists of at least four different proteins: presenilin1 (PS1) and 2 (PS2), nicastrin, Aph-1 (anterior
Vanoxerine dihydrochloride defective-1), and Pen-2 (presenilin enhancer-2) [1] and [2]. This complex cleaves key signaling molecules, including the amyloid precursor protein (APP), Notch, CD44, ErbB-4, and N (neural)- and VE (vascular endothelial)-cadherins [2], [3], [4] and [5]. Mice lacking the PS1 gene exhibit severe phenotype, characterized by late embryonic lethality which included yolk sac vasculogenesis problems [6] and [7]. It has been suggested that many of these lesions were a consequence of disturbed Notch signaling in mice [8] and [9]. γ-Secretase also released Aβ peptides with the proteolysis of the transmembrane domain of APP. Aβ peptides stimulate EC proliferation, migration, and morphogenesis in matrigel [10] and functionally synergize with fibroblast growth factor-2 (FGF-2) to promote angiogenesis in vivo [11]. Although VEGF also increases the
expression of Notch receptors and their ligands [12], it is still unknown how γ-secretase, regulator of Notch or APP signaling, contributes to VEGF-induced postnatal angiogenesis. The present study investigated the role of γ-secretase in the regulation of angiogenesis by the employing potent γ-secretase inhibitors (GSI).
