Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction

Nature Medicine volume 12, pages 841–845 (2006)Cite this article

Abstract

Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved1,2,3. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations1,2,3. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases4, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies2,5,6.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The cardiovascular system in Vav3−/− mice.
Figure 2: The RAS and endothelin systems in Vav3−/− mice.
Figure 3: SNS activity is deregulated in Vav3−/− mice.
Figure 4: Functional status of the kidneys of Vav3−/− mice.

Similar content being viewed by others

References

  1. Lifton, R.P., Gharavi, A.G. & Geller, D.S. Molecular mechanisms of human hypertension. Cell 104, 545–556 (2001).

    Article  CAS  Google Scholar 

  2. Beevers, G., Lip, G.Y. & O'Brien, E. ABC of hypertension: the pathophysiology of hypertension. Br. Med. J. 322, 912–916 (2001).

    Article  CAS  Google Scholar 

  3. Staessen, J.A., Wang, J., Bianchi, G. & Birkenhager, W.H. Essential hypertension. Lancet 361, 1629–1641 (2003).

    Article  Google Scholar 

  4. Movilla, N. & Bustelo, X.R. Biological and regulatory properties of Vav-3, a new member of the Vav family of oncoproteins. Mol. Cell. Biol. 19, 7870–7885 (1999).

    Article  CAS  Google Scholar 

  5. Palatini, P. & Julius, S. Relevance of heart rate as a risk factor in hypertension. Curr. Hypertens. Rep. 1, 219–224 (1999).

    Article  CAS  Google Scholar 

  6. Palatini, P. & Julius, S. The physiological determinants and risk correlations of elevated heart rate. Am. J. Hypertens. 12, 3S–8S (1999).

    Article  CAS  Google Scholar 

  7. Bustelo, X.R. Regulatory and signaling properties of the Vav family. Mol. Cell. Biol. 20, 1461–1477 (2000).

    Article  CAS  Google Scholar 

  8. Turner, M. & Billadeau, D.D. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat. Rev. Immunol. 2, 476–486 (2002).

    Article  CAS  Google Scholar 

  9. Faccio, R. et al. Vav3 regulates osteoclast function and bone mass. Nat. Med. 11, 284–290 (2005).

    Article  CAS  Google Scholar 

  10. Tybulewicz, V.L., Ardouin, L., Prisco, A. & Reynolds, L.F. Vav1: a key signal transducer downstream of the TCR. Immunol. Rev. 192, 42–52 (2003).

    Article  CAS  Google Scholar 

  11. Fujikawa, K. et al. Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. J. Exp. Med. 198, 1595–1608 (2003).

    Article  CAS  Google Scholar 

  12. Schmieder, R.E. & Messerli, F.H. Hypertension and the heart. J. Hum. Hypertens. 14, 597–604 (2000).

    Article  CAS  Google Scholar 

  13. Intengan, H.D. & Schiffrin, E.L. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension 38, 581–587 (2001).

    Article  CAS  Google Scholar 

  14. Takahashi, N. & Smithies, O. Gene targeting approaches to analyzing hypertension. J. Am. Soc. Nephrol. 10, 1598–1605 (1999).

    CAS  PubMed  Google Scholar 

  15. Remuzzi, G., Perico, N. & Benigni, A. New therapeutics that antagonize endothelin: promises and frustrations. Nat. Rev. Drug Discov. 1, 986–1001 (2002).

    Article  CAS  Google Scholar 

  16. DiBona, G.F. The sympathetic nervous system and hypertension: recent developments. Hypertension 43, 147–150 (2004).

    Article  CAS  Google Scholar 

  17. Carrasco, G.A. & Van de Kar, L.D. Neuroendocrine pharmacology of stress. Eur. J. Pharmacol. 463, 235–272 (2003).

    Article  CAS  Google Scholar 

  18. Palatini, P. & Julius, S. Elevated heart rate: a major risk factor for cardiovascular disease. Clin. Exp. Hypertens. 26, 637–644 (2004).

    Article  CAS  Google Scholar 

  19. Palatini, P., Benetos, A. & Julius, S. Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy. Drugs 66, 133–144 (2006).

    Article  CAS  Google Scholar 

  20. Turner, M. A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes. Immunity 7, 451–460 (1997).

  21. Jerkic, M. et al. Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J. 18, 609–611 (2004).

    Article  CAS  Google Scholar 

  22. Flores, O. et al. Beneficial effect of the long-term treatment with the combination of an ACE inhibitor and a calcium channel blocker on renal injury in rats with 5/6 nephrectomy. Exp. Nephrol. 6, 39–49 (1998).

    Article  CAS  Google Scholar 

  23. Chevillard, C., Brown, N.L., Mathieu, M.N., Laliberte, F. & Worcel, M. Differential effects of oral trandolapril and enalapril on rat tissue angiotensin-converting enzyme. Eur. J. Pharmacol. 147, 23–28 (1988).

    Article  CAS  Google Scholar 

  24. Valdivielso, J.M. et al. Renal ischemia in the rat stimulates glomerular nitric oxide synthesis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R771–R779 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Tamame, M. Blázquez, T. Iglesias, M. Jerkic and F. Núñez for technical help. We also thank V. Tybulewicz for making available to us his Vav1 knockout mice and M. Dosil for helpful comments on the manuscript. This work was supported by grants from the US National Institutes of Health to X.R.B. and the Spanish Ministry of Education and Science to X.R.B. and J.M.L.-N. V.S. is supported by a European Molecular Biology Organization (EMBO) long-term postdoctoral fellowship.

Author information

Authors and Affiliations

  1. Centro de Investigación del Cáncer, University of Salamanca, Campus Unamuno, Salamanca, E–37007, Spain

    Vincent Sauzeau, María A Sevilla, Enrique de Álava, María J Montero & Xosé R Bustelo

  2. Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca, Campus Unamuno, Salamanca, E–37007, Spain

    Vincent Sauzeau, Enrique de Álava & Xosé R Bustelo

  3. Red Temática Cooperativa de Centros de Cáncer, Consejo Superior de Investigaciones Científicas–University of Salamanca, Campus Unamuno, Salamanca, E–37007, Spain

    Vincent Sauzeau, Enrique de Álava & Xosé R Bustelo

  4. Departamento de Fisiología y Farmacología, University of Salamanca, Campus Unamuno, Salamanca, E–37007, Spain

    María A Sevilla, Juan V Rivas-Elena, María J Montero & José M López-Novoa

Authors
  1. Vincent Sauzeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María A Sevilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juan V Rivas-Elena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Enrique de Álava
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. María J Montero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José M López-Novoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xosé R Bustelo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xosé R Bustelo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Scheme of the strategy to disrupt the mouse Vav3 gene by homologous recombination. (PDF 344 kb)

Supplementary Fig. 2

Growth rates of Vav3 knockout animals. (PDF 155 kb)

Supplementary Fig. 3

Analysis of the cardiovascular defects found in Vav3−/− animals. (PDF 1420 kb)

Supplementary Fig. 4

Expression levels of the mRNAs for angiotensin II and endothelin receptors. (PDF 71 kb)

Supplementary Fig. 5

Vasopressin and aldosterone levels in Vav3−/−M animals. (PDF 77 kb)

Supplementary Table 1

Cardiovascular parameters in Vav3−/− and Vav1−/− mice. (PDF 94 kb)

Supplementary Note (PDF 115 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sauzeau, V., Sevilla, M., Rivas-Elena, J. et al. Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction. Nat Med 12, 841–845 (2006). https://doi.org/10.1038/nm1426

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1426

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing