title: Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells.
abstract: The aim of the current study was to investigate the intracellular signaling cascade that leads to temporal gradients in shear (TGS)-induced endothelial cell proliferation, with a focus on the involvement of extracellular signal-regulated kinases 1 and 2 (ERK1/2). With the use of well-defined pulsatile, impulse, step, and ramp laminar flow profiles, we found that TGS (impulse flow and pulsatile flow) induced an enhanced and sustained (>30 min) phosphorylation of ERK1/2 relative to step flow (which contains a step increase in shear followed by steady shear), whereas steady shear (ramp flow) alone downregulated activated ERK1/2. Nitric oxide (NO) was found to mediate both the stimulatory effect of TGS and the inhibitory effect of steady shear on endothelial ERK1/2 phosphorylation. Reactive oxygen species (ROS) were also demonstrated to be associated with TGS-induced ERK1/2 phosphorylation. Both G(q/11) and G(i3) were necessary for the activation of ERK1/2 by TGS. Finally, the TGS-induced endothelial proliferative response was abolished by ERK1/2 inhibition. Our study demonstrated the essential role of G proteins, NO, and ROS in TGS-dependent ERK1/2 activation and proliferative response in vascular endothelial cells.
authors.affiliation: Department of Bioengineering, University of California, La Jolla, California 92093-0412, USA.
authors.forename: X
authors.initials: X
authors.lastname: Bao
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.forename: J A
authors.initials: JA
authors.lastname: Frangos
mesh_terms: D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000502:physiology; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins