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. We have previously demonstrated that vav2 null mice suffered from serious defects in the cardiovascular system of, including tachycardia, systemic arterial hypertension, extensive cardiovascular remodelling, heart fibrosis, and loss of kidney homeostasis. By studying this hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new pathway composed of Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that is critical for nitric oxide—triggered blood vessel relaxation and normotensia. This pathway mediates the Pak—dependent inhibition of phosphodiesterase type 5, a process that favors the inactivation of the RhoA pathway and the depolymerization of the F—actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosphodiesterase type 5 requires its physical interaction with autophosphorylated Pak1 but, unexpectedly, occurs without detectable transphosphorylation events between those two proteins. The administration of phosphodiesterase type 5 inhibitors prevents the development of the hypertension and the cardiovascular disease in Vav2—deficient animals, demonstrating the key role of this signaling route in blood pressure regulation. Taken together, these results unveil the cause of the cardiovascular phenotype of Vav2 knockout animals, identify a new Rac1/Pak1 signaling element, and provide a mechanistic framework to better understand blood pressure control in physiological and pathological states.