Distinct roles for the small GTPases Cdc42 and Rho in endothelial responses to shear stress

J Clin Invest. 1999 Apr;103(8):1141-50. doi: 10.1172/JCI5367.

Abstract

Shear stress, the tangential component of hemodynamic forces, plays an important role in endothelial remodeling. In this study, we investigated the role of Rho family GTPases Cdc42 and Rho in shear stress-induced signal transduction and cytoskeleton reorganization. Our results showed that shear stress induced the translocation of Cdc42 and Rho from cytosol to membrane. Although both Cdc42 and Rho were involved in the shear stress-induced transcription factor AP-1 acting on the 12-O-tetradecanoyl-13-phorbol-acetate-responsive element (TRE), only Cdc42 was sufficient to activate AP-1/TRE. Dominant-negative mutants of Cdc42 and Rho, as well as recombinant C3 exoenzyme, attenuated the shear stress activation of c-Jun NH2-terminal kinases (JNKs), suggesting that Cdc42 and Rho regulate the shear stress induction of AP-1/TRE activity through JNKs. Shear stress-induced cell alignment and stress fiber formation were inhibited by the dominant-negative mutants of Rho and p160ROCK, but not by the dominant-negative mutant of Cdc42, indicating that the Rho-p160ROCK pathway regulates the cytoskeletal reorganization in response to shear stress.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cattle
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Cells, Cultured
  • Cytoskeleton / physiology
  • Endothelium, Vascular / cytology
  • GTP Phosphohydrolases / metabolism
  • GTP Phosphohydrolases / physiology*
  • GTP-Binding Proteins / metabolism
  • GTP-Binding Proteins / physiology*
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases*
  • Physical Stimulation
  • Protein-Serine-Threonine Kinases / metabolism
  • Response Elements
  • Transcription Factor AP-1 / metabolism
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • Transcription Factor AP-1
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein