title: Monocyte activation state regulates monocyte-induced endothelial proliferation through Met signaling.
abstract: Direct interaction of unactivated primary monocytes with endothelial cells induces a mitogenic effect in subconfluent, injured endothelial monolayers through activation of endothelial Met. We now report that monocytes' contact-dependent mitogenicity is controlled by activation-mediated regulation of hepatocyte growth factor. Direct interaction of unactivated monocytes with subconfluent endothelial cells for 12 hours resulted in 9- and 120-fold increase in monocyte tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) mRNA levels and bitemporal spike in hepatocyte growth factor that closely correlates with endothelial Met and extracellular signal-related kinase (ERK) phosphorylation. Once activated, monocytes cannot induce a second wave of endothelial cell proliferation and endothelial Met phosphorylation and soluble hepatocyte growth factor levels fall off. Monocyte-induced proliferation is dose dependent and limited to the induction of a single cell cycle. Monocytes retain their ability to activate other endothelial cells for up to 8 hours after initial interaction, after which they are committed to the specific cell. There is therefore a profoundly sophisticated mode of vascular repair. Confluent endothelial cells ensure vascular quiescence, whereas subconfluence promotes vessel activation. Simultaneously, circulating monocytes stimulate endothelial cell proliferation, but lose this potential once activated. Such a system provides for the fine balance that can restore vascular and endothelial homeostasis with minimal overcompensation.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge;
authors.forename: Shai Y
authors.initials: SY
authors.lastname: Schubert
authors.forename: Alejandro
authors.initials: A
authors.lastname: Benarroch
authors.forename: Juan
authors.initials: J
authors.lastname: Monter-Solans
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
mesh_terms: D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D053583:Interleukin-1beta; D017978:Receptors, Growth Factor; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met