Targeting eNOS and beyond: emerging heterogeneity of the role of endothelial Rho proteins in stroke protection

Expert Rev Neurother. 2009 Aug;9(8):1171-86. doi: 10.1586/ern.09.70.


Currently available modalities for the treatment of acute ischemic stroke are aimed at preserving or augmenting cerebral blood flow. Experimental evidence suggests that statins, which show 25-30% reduction of stroke incidence in clinical trials, confer stroke protection by upregulation of eNOS and increasing cerebral blood flow. The upregulation of eNOS by statins is mediated by inhibition of small GTP-binding protein RhoA. Our recent study uncovered a unique role for a Rho-family member Rac1 in stroke protection. Rac1 in endothelium does not affect cerebral blood flow. Instead, inhibition of endothelial Rac1 leads to broad upregulation of the genes relevant to neurovascular protection. Intriguingly, inhibition of endothelial Rac1 enhances neuronal cell survival through endothelium-derived neurotrophic factors, including artemin. This review discusses the emerging therapeutic opportunities to target neurovascular signaling beyond the BBB, with special emphasis on the novel role of endothelial Rac1 in stroke protection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / physiology
  • Endothelium / drug effects
  • Endothelium / metabolism
  • Endothelium / physiopathology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Models, Biological
  • Nerve Tissue Proteins / pharmacology
  • Nerve Tissue Proteins / therapeutic use*
  • Nitric Oxide Synthase Type III / metabolism*
  • Stroke* / enzymology
  • Stroke* / pathology
  • Stroke* / prevention & control
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • rhoA GTP-Binding Protein / antagonists & inhibitors
  • rhoA GTP-Binding Protein / genetics*
  • rhoA GTP-Binding Protein / metabolism


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Nerve Tissue Proteins
  • Nitric Oxide Synthase Type III
  • rhoA GTP-Binding Protein