Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
The Rho/Rac exchange factor Vav2 controls nitric oxide–dependent responses in mouse vascular smooth muscle cells
Vincent Sauzeau, … , María J. Montero, Xosé R. Bustelo
Vincent Sauzeau, … , María J. Montero, Xosé R. Bustelo
Published December 14, 2009
Citation Information: J Clin Invest. 2010;120(1):315-330. https://doi.org/10.1172/JCI38356.
View: Text | PDF
Research Article Vascular biology

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

  • Text
  • PDF
Abstract

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.

Authors

Vincent Sauzeau, María A. Sevilla, María J. Montero, Xosé R. Bustelo

×

Figure 1

Defective vasodilatation responses of renal arteries from Vav2–/– mice to NO.

Options: View larger image (or click on image) Download as PowerPoint
Defective vasodilatation responses of renal arteries from Vav2–/– mice t...
(A) Examples of real-time recordings of the response of renal arteries from the indicated mouse strains to either the single or the sequential administration (arrows) of Phe, acetylcholine (Ach), SNP, and isoproterenol. Scale bar: 10 minutes. (B) Percentage of vessel relaxation induced by the indicated doses of acetylcholine, SNP, and isoproterenol on Phe-constricted renal arteries (n = 3–7). #P < 0.05; *P < 0.01 compared with wild-type controls. log M, logarithm of the molar concentration used for each agent. Data are shown as mean ± SEM.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts