Abstract 754: Vav2 Deficiency Leads to an Angiotensin II- and Sympathetic-Dependent Cardiovascular Disease
Vav2 protein is a phosphorylation-dependent activator of Rho/Rac GTPases that is involved in both cytoskeletal and mitogenic functions that, when deregulated, promote cell transformation. Previous phenotypic studies conducted on vav2 (−/−) mice revealed a crucial role for this protein in antigen-dependent responses of B-lymphocytes. This functional specificity was intriguing, since the vav2 proto-oncogene has a wide distribution in mouse tissues. To understand the role of this protein outside the hematopoietic system, we have made a comprehensive characterization of vav2 (−/−) mice in non-hematopoietic tissues and functions. This analysis has revealed serious defects in the cardiovascular system of vav2 null mice, including tachycardia, systemic arterial hypertension, extensive cardiovascular remodelling, heart fibrosis, and loss of kidney homeostasis. These animals also show enhanced activity of both renin and angiotensinogen converting enzymes (ACE) and, as a consequence, increased levels of angiotensin II. In addition, vav2 null mice display adrenal gland hypertrophy and high noradrenaline and adrenaline plasma levels, a phenotype suggestive of sympathetic neuron hyperactivity. Treatment of vav2 (−/−) mice with either the angiotensin II AT1 receptor (losartan) or ACE inhibitors (captopril) rescues the hypertension and the cardiovascular remodelling of these animals. Interestingly, inhibition of sympathetic-dependent signalling by beta-adrenergic receptors antagonists (propranolol) also abrogates the cardiovascular and kidney defects found in vav2 (−/−) mice, indicating that the defects found in these tissues and physiological pathways are both angiotensin II- and sympathetic-dependent. These results indicate that Vav2 proteins play crucial roles outside the hematopoietic system and, specifically, in the regulation of physiological circuits controlling cardiovascular homeostasis.