title: Notch activation promotes endothelial survival through a PI3K-Slug axis.
abstract: BACKGROUND
  Loss of endothelial viability correlates with initiation and progress of vascular pathology. However, much remains to be learned about pathways required to maintain the balance between cell viability and apoptosis. Notch activation can enhance or inhibit apoptosis but its role in maintaining the endothelium needs further delineation.
  
  
  OBJECTIVE
  This study aims to identify the mechanisms by which Notch activation regulates endothelial viability.
  
  
  RESULTS
  Endothelial cells transduced with active Notch were treated with lipopolysaccharide (LPS) or homocysteine to induce endothelial apoptosis. Notch protected against LPS-induced cell death but exacerbated homocysteine-induced apoptosis. Inhibition of PI3K revealed that ligand-induced activation of endogenous Notch initiates parallel death and survival pathways and exhibits a differential effect on endothelial survival depending on the apoptotic stimulus. PI3K activity regulated the expression of Slug, which was required for survival in Notch-activated endothelial cells. Homocysteine, but not LPS, blocked both PI3K activity and Slug expression in Notch-activated cells, leading to increased endothelial apoptosis.
  
  
  CONCLUSIONS
  Notch signaling leads to activation of parallel survival and apoptotic pathways in endothelial cells. The interaction of Notch with other signaling pathways plays an important contextual role in regulating endothelial viability.
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, V5Z 1L3 BC, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.forename: Fred
authors.initials: F
authors.lastname: Wong
authors.forename: Kyle
authors.initials: K
authors.lastname: Niessen
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D017209:Apoptosis; D002470:Cell Survival; D042783:Endothelial Cells / Q000166:cytology; D004791:Enzyme Inhibitors / Q000737:chemistry; D005786:Gene Expression Regulation; D006710:Homocysteine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D008070:Lipopolysaccharides; D051880:Receptors, Notch; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D006710:Homocysteine; D019869:Phosphatidylinositol 3-Kinases
keywords: EC; HMEC; LPS; endothelial cells; human microvascular endothelial cells; lipopolysaccharides