The Notch signaling pathway. Interaction of a ligand (e.g., Delta or Jagged) with the Notch receptor (e.g., N1) initiates cleavage events at site 2 (S2) and site 3 (S3) by α- and γ-secretase, respectively, resulting in release of the intracellular domain of the receptor (NICD) from the cell membrane. NICD is then translocated into the nucleus where it forms a transcription activating complex triggering target gene (Hes, Hrt) transcription. Our data indicate that EtOH inhibits γ-secretase activity and thus, Notch signaling, in vascular SMC.