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


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.

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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.

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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.

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Correspondence to Xosé R Bustelo.

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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)

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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).

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