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

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 involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, 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 etiologies.

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

“…Tissues were dissected, fixed in 10% buffered formalin (Sigma), and embedded in paraffin; 2-to 3-μm-thick sections were stained with H&E. Antibodies used for immunohistochemistry included those to synaptophysin (1:1; Dako), GFAP (1:25; Dako), chromogranin A (1:300; Abcam), active caspase 3 (1:20; R&D Systems), and terminal deoxynucleotidyl transferase (1:15; Dako). Heart sections were stained with Sirius Red (Fluka) to visualize fibrosis (28,29).…”

“…Blood pressure and heart rates were recorded in conscious mice with an automated multichannel system using the tail-cuff method and a photoelectric sensor (Niprem 546; Cibertec SA) (29,30). Creatinine concentrations in urine and plasma were determined by a modification of Jaffé's reaction method (28,29). Adrenaline and noradrenaline levels were determined by using CatCombi ELISA kit (IBL) following the manufacturer's instructions.…”

Transcriptional Factor Aryl Hydrocarbon Receptor (Ahr) Controls Cardiovascular and Respiratory Functions by Regulating the Expression of the Vav3 Proto-oncogene

“…Animal Use-Ahr and Vav3 knock-out mice have been reported previously (25,38,45 (45,47,48), and Vav3 Ϫ/Ϫ mice and subsequent homogenization in the BL10 genetic background. Unless otherwise stated, 4-month-old mice were used in experiments.…”

“…This gene encodes a tyrosine phosphorylation GDP/GTP exchange factor for Rho/Rac family GTPases that plays important roles in cytoskeletonlinked signaling events activated by transmembrane and/or cytoplasmic tyrosine kinases (36,37). Recent genetic experiments using knock-out mice have revealed that this GDP/ GTP exchange factor is important for cardiovascular homeostasis (38), adequate control of sympathetic activity (38), the timely development of the cerebellum in early postnatal stages (39), and axon guidance events in inhibitory GABAergic cells of the VLM (40), a brainstem region involved in the coordinated control of cardiovascular, respiratory, adrenal, and renal activities (41,42). Cooperating with other Vav family members (Vav1 and Vav2), Vav3 also participates in the development, selection, and antigen responses of lymphocytes (43), the effector functions of other hematopoietic lineages, angiogenesis (43), and axon guidance events (44).…”

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

“…19 At least 30 cardiomyocytes were measured per heart, and the average was used for analysis. The percentage area of interstitial fibrosis in the LV at the papillary muscle level in the slides stained with the sirius red stain was determined as described earlier, 18,19,[25][26][27][28] using a commercially available computer software (Mac scope v 2.5, Mitani, Fukui, Japan).…”