The Rho/Rac exchange factor Vav2 controls nitric oxide–dependent responses in mouse vascular smooth muscle cells
Vincent Sauzeau, María A. Sevilla, María J. Montero, Xosé R. Bustelo
Vincent Sauzeau, María A. Sevilla, María J. Montero, Xosé R. Bustelo
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Research Article Vascular biology

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

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

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Figure 11

Blood pressure and cardiovascular parameters in sildenafil-treated Vav2–/– mice.

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Blood pressure and cardiovascular parameters in sildenafil-treated Vav2–...
(A) Arterial pressure (left panel n = 5–9), heart rates (middle panel n = 5–9), and plasma levels of angiotensin II (right panel n = 5–9) in 4-month-old mice of the indicated genotypes that were either untreated (–) or treated (+) with sildenafil for 4 months. #P < 0.05; *P < 0.01 compared with wild-type controls. (B) Histological sections of aortas (2 left columns) and hearts (2 right columns) of 4-month-old mice of the indicated genotypes, which were previously left untreated (–) or treated (+) with sildenafil for 4 months as indicated. Asterisks mark the aortic media walls and the left heart ventricles. Sections are representative samples of 5 mice of each genotype. Scale bars: 100 μm (arteries); 1 mm (hearts). (C) Size of the aorta media wall (upper panel) and myocytes (lower panel) from 4-month-old animals of the indicated genotypes treated (+) or untreated (–) with sildenafil for 4 months (n = 5). *P < 0.01 compared with wild-type controls. Data are shown as mean + SEM. (D) Schematic representation of the new pathway reported in this work (blue color). The previously known signaling elements and connections of the NO signaling route in vSMCs are shown in black. Activation steps are indicated by arrows. Inhibitory steps are indicated by blunted lines. Putative connections among molecules are indicated as broken lines.