The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells

J Clin Invest. 2010 Jan;120(1):315-30. doi: 10.1172/JCI38356. Epub 2009 Dec 14.


The regulation of arterial contractility is essential for blood pressure control. The GTPase RhoA promotes vasoconstriction by modulating the cytoskeleton of vascular smooth muscle cells. Whether other Rho/Rac pathways contribute to blood pressure regulation remains unknown. By studying a hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide-triggered blood vessel relaxation and normotensia. This pathway mediated the Pak-dependent inhibition of phosphodiesterase type 5, a process that favored RhoA inactivation and the subsequent depolymerization of the F-actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosphodiesterase type 5 required its physical interaction with autophosphorylated Pak1 but, unexpectedly, occurred without detectable transphosphorylation events between those 2 proteins. The administration of phosphodiesterase type 5 inhibitors prevented the development of hypertension and cardiovascular disease in Vav2-deficient animals, demonstrating the involvement of this new pathway in blood pressure regulation. Taken together, these results unveil one cause of the cardiovascular phenotype of Vav2-knockout mice, identify a new Rac1/Pak1 signaling pathway, and provide a mechanistic framework for better understanding blood pressure control in physiological and pathological states.

Publication types

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

MeSH terms

  • Animals
  • Cyclic GMP / biosynthesis
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / physiology
  • Hypertension / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / physiology*
  • Myocytes, Smooth Muscle / physiology*
  • Neuropeptides / physiology
  • Nitric Oxide / physiology*
  • Phosphodiesterase 5 Inhibitors
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-vav / physiology*
  • Purines / pharmacology
  • Signal Transduction
  • Sildenafil Citrate
  • Sulfones / pharmacology
  • Vasodilation
  • p21-Activated Kinases / physiology
  • rac GTP-Binding Proteins / physiology
  • rac1 GTP-Binding Protein
  • rho-Associated Kinases / physiology
  • rhoA GTP-Binding Protein / physiology


  • Neuropeptides
  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Proto-Oncogene Proteins c-vav
  • Purines
  • Rac1 protein, mouse
  • Sulfones
  • Vav2 protein, mouse
  • Vav3 protein, mouse
  • Nitric Oxide
  • Sildenafil Citrate
  • Pak1 protein, mouse
  • p21-Activated Kinases
  • rho-Associated Kinases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein
  • Cyclic GMP